4-(phenoxyalkyl)thio)-phenoxyacetic acids and analogs

ABSTRACT

The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs, compositions containing them, and methods of using them as PPAR delta modulators to treat or inhibit the progression of, for example, dyslipidemia.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a divisional of U.S. patent application Ser. No.12/623,824, filed Nov. 23, 2009, which is a divisional application ofU.S. application Ser. No. 11/872,417, filed Oct. 15, 2007, now U.S. Pat.No. 7,635,718, which is a divisional of U.S. application Ser. No.10/942,478, filed Sep. 16, 2004, now U.S. Pat. No. 7,301,050, whichclaims priority to U.S. Provisional Patent Application No. 60/504,146,filed Sep. 19, 2003, the disclosures of which are hereby incorporated byreference in their entireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

Cardiovascular disease (CVD) is prevalent in the world and is oftenassociated with other disease states such as diabetes and obesity. Manypopulation studies have attempted to identify the risk factors for CVD;of these, high plasma levels of low density lipoprotein cholesterol(LDL-C), high plasma levels of triglycerides (>200 mg/dI), and lowlevels of high density lipoprotein cholesterol (HDL-C) are considered tobe among the most important. Currently, there are few therapiestargeting low HDL-C and triglycerides.

The peroxisome proliferator-activated receptors (PPARs) are metabolicsensors regulating the expression of genes involved in glucose and lipidhomeostasis. Agonists of the PPARα subtype, such as LOPID® (gemfibrozil)and TRICOR® (fenofibrate), and agonists of the PPARγ subtype, such asAVANDIA® (rosiglitazone maleate), are used for the treatment ofdyslipidemia and diabetes, respectively. Another member of this nuclearreceptor family, the peroxisome proliferator-activated receptor delta(PPAR delta or PPARδ) is also a necessary transcription factor reportedto be involved in regulating genes involved in lipid metabolism andenergy expenditure. PPAR delta has been shown to act as a ‘gateway’receptor modulating the expression of the other PPARs (Shi et al., 2002,Proc Natl. Acad. Sci. USA, 99(5): 2613-2618). Each receptor subtype hasa distinct tissue distribution: 1) PPARα shows the highest expression inliver, 2) PPARγ appears primarily in adipose tissue, and 3) PPARδ hasthe widest distribution—ubiquitously in adult rat (Braissant et al.,1996, Endocrinology 137(1): 354-366) and in all the human tissues testedto date, including liver, kidney, abdominal adipose and skeletal muscle(Auboeuf et al., 1997, Diabetes 46(8):1319-1327).

Recently, potent ligands for PPARδ have been published, providing abetter understanding of its function in lipid metabolism. The maineffect of these compounds in db/db mice (Leibowitz et al., 2000, FEBSLett. 473(3):333-336) and obese rhesus monkeys (Oliver et al., 2001,Proc. Natl. Acad. Sci. USA 98(9):5306-5311) was an increase in highdensity lipoprotein cholesterol (HDL-C) and a decrease in triglycerides,with little effect on glucose (although insulin levels were decreased inmonkeys). HDL-C removes cholesterol from peripheral cells through aprocess called reverse cholesterol transport. The first andrate-limiting step, a transfer of cellular cholesterol and phospholipidsto the apolipoprotein A-I component of HDL, is mediated by the ATPbinding cassette transporter A1 (ABCA1) (Lawn et al., 1999, J. Clin.Investigation 104(8): R25-R31). PPARδ activation has been shown toincrease HDL-C level through transcriptional regulation of ABCA1 (Oliveret al., 2001, Proc. Natl. Acad. Sci. USA 98(9): 5306-5311). Throughinduction of ABCA1 mRNA expression in macrophages, PPARδ agonists mayincrease HDL-C levels in patients and remove excess cholesterol fromlipid-laden macrophages, thereby inhibiting the development ofatherosclerotic lesions. Existing therapy for hypercholesterolemiaincludes the statin drugs, which decrease LDL-C but show little effecton HDL-C, and the fibrates, the PPARα agonists that have low potency andinduce only modest HDL-C elevation. In addition, like the fibrates,PPARδ agonists may also reduce triglycerides, an additional risk factorfor cardiovascular disease and diabetes. Elevated free fatty acid levelhas been shown to contribute to insulin resistance and progression ofdiabetes (Boden, G. PROCEEDINGS OF THE ASSOCIATION OF AMERICANPHYSICIANS (1999 May-June), 111(3), 241-8).

Examples of known PPAR delta agonists variously useful forhyperlipidemia, diabetes, or atherosclerosis include L-165041 (Leibowitzet al., 2000) and GW501516 (Oliver et al., Proceedings of the NationalAcademy of Sciences of the United States of America (2001), 98(9),5306-5311). Treatment of differentiated THP-1 monocytes with GW501516induced ABCA1 mRNA expression and enhanced cholesterol efflux from thesecells.

SUMMARY OF THE INVENTION

The invention features compounds of Formula (I) below:

wherein

-   -   X is selected from a covalent bond, S, or O;    -   Y is S or O;    -   - - - - - W - - - - - represents a group selected from ═CH—,        —CH═, —CH₂—, —CH₂—CH₂—, ═CH—CH₂—, —CH₂—CH═, ═CH—CH═, and        —CH═CH—;    -   Z is selected from O, CH, and CH₂, provided when Y is O, Z is O;    -   R₁ and R₂ are independently selected from H, C₁₋₃alkyl, C₁₋₃        alkoxy, halo, and NR_(a)R_(b) wherein R_(a) and R_(b) are        independently H or C₁₋₃ alkyl;    -   R₃ and R₄ are independently selected from H, halo, cyano,        hydroxy, acetyl, C₁₋₅ alkyl, C₁₋₄ alkoxy, and NR_(c)R_(d)        wherein R_(c) and R_(d) are independently H or C₁₋₃ alkyl,        provided that R₃ and R₄ are not both H;    -   R₅ is selected from halo, phenyl, phenoxy, (phenyl)C₁₋₅alkoxy,        (phenyl)C₁₋₅alkyl, C₂₋₅heteroaryloxy, C₂₋₅heteroarylC₁₋₅alkoxy,        C₂₋₅heterocyclyloxy, C₁₋₉ alkyl, C₁₋₈ alkoxy, C₂₋₉ alkenyl, C₂₋₉        alkenyloxy, C₂₋₉ alkynyl, C₂₋₉ alkynyloxy, C₃₋₇ cycloalkyl, C₃₋₇        cycloalkoxy, C₃₋₇cycloalkyl-C₁₋₇alkyl,        C₃₋₇cycloalkyl-C₁₋₇alkoxy, C₃₋₇cycloalkyloxy-C₁₋₆alkyl,        C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₅alkoxy-C₁₋₅alkoxy, or        C₃₋₇cycloalkyloxy-C₁-C₇alkoxy;    -   R₆ is H when - - - - - W - - - - - represents a group selected        from —CH═, —CH₂—, —CH₂—CH₂—, —CH₂—CH═, and —CH═CH—,    -   or R₆ is absent when - - - - - W - - - - - represents a group        selected from ═CH—, ═CH—CH₂—, and ═CH—CH═; and    -   n is 1 or 2;        or a pharmaceutically acceptable salt thereof.

The invention also features compositions that include one or morecompounds of Formula (I) and a pharmaceutical carrier or excipient.

These compositions and the methods below may further include additionalpharmaceutically active agents, such as lipid-lowering agents orblood-pressure lowering agents, or both.

Another aspect of the invention includes methods of using the disclosedcompounds or compositions in various methods for treating, preventing,or inhibiting the progression of, a condition directly or indirectlymediated by PPAR delta. Said condition includes, but is not limited to,diabetes, cardiovascular diseases, Metabolic X Syndrome,hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity.

One embodiment of the present invention is a method for treating aPPAR-delta mediated condition, said method comprising administering to apatient in need of treatment a pharmaceutically effective amount of acompound or composition described herein.

Another embodiment of the present invention is a method for inhibitingthe onset and/or inhibiting the progression of a PPAR-delta mediatedcondition, said method comprising administering to a patient in need oftreatment a pharmaceutically effective amount of a compound orcomposition described herein.

Examples of conditions that can be treated with a PPAR delta-agonistinclude, without limitation, diabetes, cardiovascular diseases,Metabolic X Syndrome, hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity.Dyslipidemia includes hypertriglyceridemia, and mixed hyperlipidemia.For example, dyslipidemia (including hyperlipidemia) may be one or moreof the following conditions: low HDL (<35 or 40 mg/dl), hightriglycerides (>200 mg/dl), and high LDL (>150 mg/dl).

Additional features and advantages of the invention will become apparentfrom the detailed discussion, examples, and claims below.

DETAILED DESCRIPTION

The invention features compositions containing compounds of Formula (I)in the above Summary section, and methods of using them.

Preferred compounds of the invention are potent PPAR delta agonists thathave at least one and preferably two or three of the followingcharacteristics when administered to patients with hypercholesterolemia,hypertriglyceridemia, low-HDL-C, obesity, diabetes and/or Metabolic XSyndrome: 1) increasing HDL-C level, 2) lowering triglycerides, 3)lowering free fatty acids, and 4) decreasing insulin levels. Improvementin HDL-C and triglyceride levels is beneficial for cardiovascularhealth. In addition, decreased level of triglycerides and free fattyacids contributes to reduce obesity and ameliorate or prevent diabetes.

PPAR delta, being ubiquitously expressed, can act as a gateway receptorthat regulates the expression/activity of other nuclear receptors suchas other PPARs. For instance, PPAR delta has been shown to blockPPARγ-mediated adipogenesis and acyl-CoA oxidase expression; it has alsobeen shown to be associated with the nuclear receptor corepressors SMRT(silencing mediator for retinoid and thyroid hormone receptors), SHARP(SMART and histone deacetylase-associated repressor protein), and HDACs(histone deacetylase). Thus, conditions directly mediated by thesenuclear receptors, such as obesity and type II diabetes, can beindirectly mediated by PPAR delta (See, for example, Shi et al., 2002,Proc Natl. Acad. Sci. USA, 99(5): 2613-2618).

Some aspects of the invention relate to treating hypertriglyceridemia,raising levels of HDL, lowering levels of LDL, and/or lowering totalcholesterol. Preferably, the methods of treatment are associated withimprovements in the extent, duration, or degree of side effects, such asedema, normally associated with other existing therapies.

The invention is further described below. The specification is arrangedas follows: A) Terms; B) Compounds; C) Synthesis; D) Formulation andAdministration; E) Use; F) Biological Examples; G) Other Embodiments;and claims.

A. Terms

The term ‘subject’ as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term ‘therapeutically effective amount’ as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation, prevention, treatment, orthe delay of the onset or progression of the symptoms of the disease ordisorder being treated.

Conditions directly or indirectly mediated by PPAR delta include, butare not limited to, diabetes, cardiovascular diseases, Metabolic XSyndrome, hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity.

For therapeutic purposes, the term ‘jointly effective amount’ as usedherein, means that amount of each active compound or pharmaceuticalagent, alone or in combination, that elicits the biological or medicinalresponse in a tissue system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician, whichincludes alleviation of the symptoms of the disease or disorder beingtreated. For prophylactic purposes (i.e., inhibiting the onset orprogression of a disorder), the term ‘jointly effective amount’ refersto that amount of each active compound or pharmaceutical agent, alone orin combination, that treats or inhibits in a subject the onset orprogression of a disorder as being sought by a researcher, veterinarian,medical doctor or other clinician. Thus, the present invention providescombinations of two or more drugs wherein, for example, (a) each drug isadministered in an independently therapeutically or prophylacticallyeffective amount; (b) at least one drug in the combination isadministered in an amount that is sub-therapeutic or sub-prophylactic ifadministered alone, but is therapeutic or prophylactic when administeredin combination with the second or additional drugs according to theinvention; or (c) both (or more) drugs are administered in an amountthat is sub-therapeutic or sub-prophylactic if administered alone, butare therapeutic or prophylactic when administered together.

Unless otherwise noted, as used herein and whether used alone or as partof a substituent group, ‘alkyl’ and ‘alkoxy’ include straight andbranched chains having 1 to 8 carbon atoms, such as C₁₋₆, C₁₋₄, C₃₋₈,C₂₋₅, or any other range, and unless otherwise noted, include bothsubstituted and unsubstituted moieties. For example, C₁₋₆alkyl radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl,2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxyradicals are formed from the previously described straight or branchedchain alkyl groups. ‘Alkyl’ and ‘alkoxy’ include unsubstituted orsubstituted moieties with one or more substitutions, such as between 1and 5, 1 and 3, or 2 and 4 substituents. The substituents may be thesame (dihydroxy, dimethyl), similar (chloro, fluoro), or different(chlorobenzyl-or aminomethyl-substituted). Examples of substituted alkylinclude haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl,perchloromethyl, 2-bromoethyl, trifluoromethyl, and 3-iodocyclopentyl),hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl),aminoalkyl (such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and2-aminopropyl), alkoxylalkyl, nitroalkyl, alkylalkyl, cyanoalkyl,phenylalkyl, heteroarylalkyl, heterocyclylalkyl, phenoxyalkyl,heteroaryloxyalkyl (such as 2-pyridyloxyalkyl), heterocyclyloxy-alkyl(such as 2-tetrahydropyranoxy-alkyl), thioalkylalkyl (such asMeS-alkyl), thiophenylalkyl (such as phS-alkyl), carboxylalkyl, and soon. A di(C₁₋₃ alkyl)amino group includes independently selected alkylgroups, to form, for example, methylpropylamino andisopropylmethylamino, in addition dialkylamino groups having two of thesame alkyl group such as dimethyl amino or diethylamino.

The term ‘alkenyl’ includes optionally substituted straight chain andbranched hydrocarbon radicals as above with at least one carbon-carbondouble bond (sp²). Alkenyls include ethenyl (or vinyl), prop-1-enyl,prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl,but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenylincludes cycloalkenyl. Cis and trans or (E) and (Z) forms are includedwithin the invention. ‘Alkenyl’ may be substituted with one or moresubstitutions including, but not limited to, cyanoalkenyl, andthioalkenyl.

The term ‘alkynyl’ includes optionally substituted straight chain andbranched hydrocarbon radicals as above with at least one carbon-carbontriple bond (sp).

Alkynyls include ethynyl, propynyls, butynyls, and pentynyls.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl doesnot include cycloalkynyl.

The term ‘Ac’ as used herein, whether used alone or as part of asubstituent group, means acetyl (CH₃CO—).

The term ‘halogen’ or ‘halo’ shall include iodo, bromo, chloro andfluoro.

The terms ‘aryl’ or ‘Ar’ as used herein refer to an unsubstituted orsubstituted aromatic hydrocarbon ring system such as phenyl andnaphthyl. When the Ar or aryl group is substituted, it may have one tothree substituents which are independently selected from C₁-C₈ alkyl,C₁-C₈ alkoxy, fluorinated C₁-C₈ alkyl (e.g., trifluoromethyl),fluorinated C₁-C₈ alkoxy (e.g., trifluoromethoxy), halogen, cyano, C₁-C₈alkylcarbonyl such as acetyl, carboxyl, hydroxy, amino, nitro, C₁-C₄alkylamino (i.e., —NH—C₁-C₄ alkyl), C₁-C₄ dialkylamino (i.e., —N-[C₁-C₄alkyl]₂ wherein the alkyl groups can be the same or different), orunsubstituted, mono-, di-or tri-substituted phenyl wherein thesubstituents on the phenyl are independently selected from C₁-C₈ alkyl,C₁-C₈ alkoxy, fluorinated C₁-C₈ alkyl, fluorinated C₁-C₈ alkoxy,halogen, cyano, acetyl, carboxyl, hydroxy, amino, nitro, alkylamino,dialkylamino or five or six membered heteroaryl having 1-3 heteroatomsselected from N, O and S.

The term ‘heteroaryl’ as used herein represents a stable, unsubstitutedor substituted five or six membered monocyclic or bicyclic aromatic ringsystem which consists of carbon atoms and from one to three heteroatomsselected from N, O and S. The heteroaryl group may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of heteroaryl groups include, but are not limitedto, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzopyrazolyl,benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl,benzoxazolyl, furanyl, furazanyl, furyl, imidazolyl, indazolyl,indolizinyl, indolinyl, indolyl, isobenzofuranyl, isoindolyl,isothiazolyl, isoxazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, quinolyl,thiadiazolyl, thiazolyl, thiophenyl, or triazolyl. When the heteroarylgroup is substituted, the heteroaryl group may have one to threesubstituents including, but not limited to, C₁-C₈ alkyl, halogen, andaryl.

The term ‘heterocyclyl’ includes optionally substituted nonaromaticrings having carbon atoms and at least one heteroatom (O, S, N) orheteroatom moiety (SO₂, CO, CONN, COO) in the ring. A heterocyclyl maybe saturated, partially saturated, nonaromatic, or fused. Examples ofheterocyclyl include cyclohexylimino, imdazolidinyl, imidazolinyl,morpholinyl, piperazinyl, piperidyl, pyridyl, pyranyl, pyrazolidinyl,pyrazolinyl, pyrrolidinyl, pyrrolinyl, and thienyl.

Unless otherwise indicated, heteroaryl and heterocyclyl may have avalence connecting it to the rest of the molecule through a carbon atom,such as 3-furyl or 2-imidazolyl, or through a heteroatom, such asN-piperidyl or 1-pyrazolyl. Preferably a monocyclic heterocyclyl hasbetween 5 and 7 ring atoms, or between 5 and 6 ring atoms; there may bebetween 1 and 5 heteroatoms or heteroatom moieties in the ring, andpreferably between 1 and 3, or between 1 and 2 heteroatoms or heteroatommoieties.

Heterocyclyl and heteroaryl also include fused, e.g., bicyclic, rings,such as those optionally fused with an optionally substitutedcarbocyclic or heterocyclic five-or six-membered aromatic ring. Forexample, ‘heteroaryl’ includes an optionally substituted six-memberedheteroaromatic ring containing 1, 2 or 3 nitrogen atoms fused with anoptionally substituted five-or six-membered carbocyclic or heterocyclicaromatic ring. Said heterocyclic five-or six-membered aromatic ringfused with the said five-or six-membered aromatic ring may contain 1, 2or 3 nitrogen atoms where it is a six-membered ring, or 1, 2 or 3heteroatoms selected from oxygen, nitrogen and sulfur where it is afive-membered ring.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Where chemical moieties are combined, such as in ethoxymethyl orphenylethyl, the term is described in the direction from the peripheryto the connection point of the rest of the molecule. For example,ethoxymethyl is CH₃CH₂OCH₂— and phenylethyl is a phenyl group linked by—CH₂CH₂— to the rest of the molecule (and not a phenyl group linked tothe molecule with a CH₃CH₂ group as a substituent on the phenyl.) Whereparentheses are used, they indicate a peripheral substitution.

As used herein, the term ‘composition’ is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Compounds of the invention are further described in the next section.

B. Compounds

The present invention features compositions containing and methods ofusing compounds of Formula (I) as described above. Unless otherwisenoted, in Formula (I), each hydrocarbyl (alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, etc) or heterocarbyl (heterocyclyl,heteroaryl, heteroatom moiety such as sulfonyl, amino, amido, etc.) maybe substituted or unsubstituted, for example, ‘alkyl’ includessubstituted and unsubstituted alkyl and ‘heterocyclyl’ and ‘aryl’ and‘alkoxy’ and so on, may also be substituted or unsubstituted.

Examples of the present invention include those compounds wherein: (a) Xis S or O; (b) X is a covalent bond; (c) X is O; (d) Y is O; (e) Y is S;(f) Z is O; (g) Z is CH or CH₂; (h) W represents —CH₂— or CH₂—CH₂—;(i) - - - - - W - - - - - represents —CH₂—; (j) - - - - - W - - - - -represents ═CH—, —CH═, ═CH—CH₂—, —CH₂—CH═, ═CH—CH═, or —CH═CH—; (k) R₁and R₂ are independently selected from H, C₁₋₃ alkyl, C₁₋₃ alkoxy, F,Cl, and Br; (I) R₃ and R₄ are independently selected from H, halo,cyano, C₁₋₄ alkyl, and C₁₋₃ alkoxy; (m) R₁ and R₂ are independentlyselected from H, methyl, methoxy, F and Cl; (n) R₃ and R₄ areindependently selected from H, halo, cyano, hydroxy, C₂₋₄ acyl, C₁₋₄alkyl, and C₁₋₃ alkoxy; (o) R₃ is independently selected from H, F, Cl,methyl, and methoxy; (p) R₄ is independently selected from F, Cl,methyl, methoxy, trifluoromethyl, fluoromethyl, difluoromethyl,chlorodifluoromethyl, dichlorofluoromethyl, fluoromethoxy,difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy andtrifluoromethoxy; (q) R₃ is selected from methyl, methoxy, H, Cl, Br, I,OH, —CH(CF₃)₂, CF₃, —OCF₃, —N(CH₃)₂, —O—CH₂COOH, and —COCH₃, and R₄ isselected from H, Cl, and methyl; (r) R₅ is selected from C₁₋₇ alkyl,C₁₋₆ alkoxy, C₂₋₇ alkenyl, C₂₋₇ alkenyloxy, C₂₋₇ alkynyl, C₂₋₇alkynyloxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy, C₁₋₆alkoxy-C₁₋₆alkyl,C₁₋₅alkoxy-C₁₋₅alkoxy, and C₃₋₇cycloalkyloxy-C₁₋₇alkoxy; (s) R₅ isselected from and phenoxy, (phenyl)C₁₋₅alkoxy, (Phenyl)C₁₋₅alkyl,C₂₋₅heteroaryloxy, C₂₋₅heteroarylC₁₋₅alkoxy, C₂₋₅heterocyclyloxy,C₃₋₇cycloalkyl-C₁₋₇alkyl, C₃₋₇cycloalkyl-C₁₋₇alkoxy, andC₃₋₇cycloalkyloxy-C₁₋₆alkyl; (t) R₆ is H; (u) R₃ is selected from H, F,Cl, methyl, and methoxy, and R₄ is selected from F, Cl, methyl,fluoromethyl, difluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethyl, trifluoromethoxy, and methoxy; (v) R₁ is selected fromH, CF₃, methyl, Cl, and methoxy, and R₂ is selected from H, Cl, andmethyl; (w) R₁ is selected from H, CF₃, methyl, Cl, and methoxy, and R₂is selected from H, Cl, and methyl, and X is a covalent bond; (x) R₁ isselected from H, CF₃, methyl, Cl, and methoxy, and R₂ is selected fromH, Cl, and methyl, X is covalent bond, Y is S, and Z is O; (y) X is Oand Y is O; (z) X is O and Y is S; (aa) Y is O and Z is O; (bb) Y is Sand Z is O; (cc) R₆ is H and R₅ is selected from C₁₋₇ alkyl, C₁₋₆alkoxy, C₂₋₇ alkenyl, C₂₋₇ alkenyloxy, C₁₋₆alkoxy-C₁₋₆alkyl, andC₁₋₅alkoxy-C₁₋₅alkoxy; (dd) R₆ is H and R₅ is selected from C₁₋₆ alkyl,C₁₋₄ alkoxy, C₂₋₅ alkenyl, C₂₋₅ alkenyloxy, and C₁₋₅alkoxy-C₁₋₅alkoxy;(ee) R₆ is H and R₅ is selected from C₁₋₃ alkyl, C₁₋₃ alkoxy, C₂₋₄alkenyl, C₂₋₄ alkenyloxy, and C₁₋₃alkoxy-C₁₋₃alkoxy; (ff) R₆ is H and R₅is selected from methoxy, ethoxy, propoxy, isopropoxy, propenyloxy,isopropenyloxy, ethoxy-methoxy, methoxy-methoxy, methoxy-methyl,methoxyethyl, ethoxymethyl, and ethoxy-ethyl; (gg) R₁ is selected fromH, CF₃, methyl, Cl, and methoxy, R₂ is selected from H, Cl, and methyl,R₃ is selected from H, F, Cl, methyl, and methoxy; and R₄ is selectedfrom F, Cl, methyl, trifluoromethyl, trifluoromethoxy, fluoromethyl,fluoromethoxy, difluoromethyl, difluoromethoxy, and methoxy; (hh) X isO, Y is O, R₃ is selected from H, F, Cl, methyl, and methoxy; and R₄ isselected from F, Cl, methyl, CF₃, OCF₃ and methoxy; (ii) X is O, Y is S,R₃ is selected from H, F, Cl, methyl, and methoxy, and R₄ is selectedfrom F, Cl, methyl, CF₃, OCF₃ and methoxy; (jj) X is covalent bond, Y isS, R₃ is selected from H, F, Cl, methyl, and methoxy, and R₄ is selectedfrom F, Cl, methyl, CF₃, OCF₃, and methoxy; (kk) Y is O, Z is O, R₃ isselected from H, F, Cl, methyl, and methoxy; and R₄ is selected from F,Cl, methyl, CF₃, OCF₃ and methoxy; (II) Y is S, Z is O, R₃ is selectedfrom H, F, Cl, methyl, and methoxy, and R₄ is selected from F, Cl,methyl, CF₃, OCF₃ and methoxy; (mm) R₃ is selected from H, F, Cl,methyl, and methoxy, R₄ is selected from F, Cl, methyl, CF₃, OCF₃, andmethoxy, R₅ is selected from C₁₋₇ alkyl, C₁₋₆ alkoxy, C₂₋₇ alkenyl, C₂₋₇alkenyloxy, C₁₋₆alkoxy-C₁₋₆alkyl, and C₁₋₅alkoxy-C₁₋₅alkoxy and R₆ is H;(nn) X is O, Y is O, R₅ is selected from C₁₋₃ alkyl, C₁₋₃ alkoxy, C₂₋₄alkenyl, C₂₋₄ alkenyloxy, and C₁₋₃alkoxy-C₁₋₃alkoxy, and R₆ is H; (O) Xis O, Y is S, R₅ is selected from C₁₋₃ alkyl, C₁₋₃ alkoxy, C₂₋₄ alkenyl,C₂₋₄ alkenyloxy, and C₁₋₃alkoxy-C₁₋₃alkoxy, and R₆ is H; (pp) X is O, Yis O, R₁ is selected from H, CF₃, methyl, Cl, and methoxy, R₂ isselected from H, Cl, and methyl, R₃ is selected from H, F, Cl, methyl,and methoxy, R₄ is selected from F, Cl, methyl, CF₃, OCF₃ and methoxy,and n is 1; (qq) X is O, Y is S, R₁ is selected from H, CF₃, methyl, Cl,and methoxy, R₂ is selected from H, Cl, and methyl, R₃ is selected fromH, F, Cl, methyl, and methoxy, and R₄ is selected from F, Cl, methyl,CF₃, OCF₃ and methoxy; (rr) X is O, Y is S, R₁ is selected from H, CF₃,methyl, Cl, and methoxy, R₂ is selected from H, Cl, and methyl, R₃ isselected from H, F, Cl, methyl, and methoxy, R₄ is selected from F, Cl,methyl, CF₃, OCF₃ and methoxy, and n=1; or (ss) X is O, Y is S, R₁ isselected from H, CF₃, methyl, Cl, and methoxy, R₂ is selected from H,Cl, and methyl, R₃ is selected from H, F, Cl, methyl, and methoxy, R₄ isselected from F, Cl, methyl, CF₃, OCF₃ and methoxy, R₅ is selected fromC₁₋₃ alkyl, C₁₋₃ alkoxy, C₂₋₄ alkenyl, C₂₋₄ alkenyloxy, andC₁₋₃alkoxy-C₁₋₃alkoxy, R₆ is H, and n=1; or combinations of the above.

According to another aspect of the invention, Formula (I) is modifiedsuch that - - - - - W - - - - - can also be a covalent bond, and R₆ is Hwhen - - - - - W - - - - - represents a group selected from a covalentbond, —CH═, —CH₂—, —CH₂—CH₂—, —CH₂—CH═, and —CH═CH—, or R₆ is absentwhen - - - - - W - - - - - represents a group selected from ═CH—,═CH—CH₂—, and ═CH—CH═.

Particularly, examples of Formula (I) include those compounds wherein:(a) X is O and Y is O; (b) X is a covalent bond and R₁ is selected fromH, CF₃, methyl, Cl, and methoxy, and R₂ is selected from H, Cl, andmethyl; (c) X is O and Y is S; (d) X is covalent bond, Y is S and Z isO; (e) Y is S and Z is O; (f) Y is O and Z is O; (g) R₁ is selected fromH, CF₃, methyl, Cl, and methoxy, and R₂ is selected from H, Cl, andmethyl; (h) R₁ and R₂ are independently selected from H, methyl,methoxy, F and Cl; (i) R₃ is independently selected from H, F, Cl,methyl, and methoxy; a) R₄ is independently selected from F, Cl, methyl,methoxy, trifluoromethyl, fluoromethyl, difluoromethyl,chlorodifluoromethyl, dichlorofluoromethyl, fluoromethoxy,difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy andtrifluoromethoxy; (k) R₃ is selected from methyl, methoxy, H, Cl, Br, I,OH, —CH(CF₃)₂, CF₃, —OCF₃, —N(CH₃)₂, —O—CH₂COOH, and —COCH₃, and R₄ isselected from H, Cl, and methyl; (l) R₃ is selected from H, F, Cl,methyl, and methoxy, and R₄ is selected from F, Cl, methyl,fluoromethyl, difluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethyl, trifluoromethoxy, and methoxy; (m) R₅ is selected fromC₁₋₇ alkyl, C₁₋₆ alkoxy, C₂₋₇ alkenyl, C₂₋₇ alkenyloxy, C₂₋₇ alkynyl,C₂₋₇ alkynyloxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy,C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkoxy, andC₃₋₇cycloalkyloxy-C₁₋₇alkoxy; (n) R₆ is H and R₅ is selected from C₁₋₇alkyl, C₁₋₆ alkoxy, C₂₋₇ alkenyl, C₂₋₇ alkenyloxy, C₁₋₆alkoxy-C₁₋₆alkyl,and C₁₋₆alkoxy-C₁₋₆alkoxy; (o) R₆ is H and R₅ is selected from C₁₋₆alkyl, C₁₋₄ alkoxy, C₂₋₅ alkenyl, C₂₋₅ alkenyloxy, andC₁₋₆alkoxy-C₁₋₆alkoxy; (p) R₆ is H and R₅ is selected from C₁₋₃ alkyl,C₁₋₃ alkoxy, C₂₋₄ alkenyl, C₂₋₄ alkenyloxy, and C₁₋₃alkoxy-C₁₋₃alkoxy;(q) R₆ is H and R₅ is selected from methoxy, ethoxy, propoxy,isopropoxy, propenyloxy, isopropenyloxy, ethoxy-methoxy,methoxy-methoxy, methoxy-methyl, methoxyethyl, ethoxymethyl, andethoxy-ethyl; or - - - - - W - - - - - represents a covalent bond; orcombinations of the above.

In another example, compounds of the present invention can be those ofFormula (II):

wherein

-   -   X is selected from a covalent bond, S, or O;    -   Y is S or O;    -   - - - - - W - - - - - represents a group selected from —CH═,        —CH₂—, —CH₂—CH₂—, —CH₂—CH═, and —CH═CH—;    -   Z is selected from O, CH, and CH₂, provided when Y is O, Z is O;    -   R₁ and R₂ are independently selected from H, C₁₋₃ alkyl, C₁₋₃        alkoxy, halo, and NR_(a)R_(b) wherein R_(a) and R_(b) are        independently H or C₁₋₃ alkyl;    -   R₃ and R₄ are independently selected from H, halo, cyano,        hydroxy, acetyl, C₁₋₅ alkyl, C₁₋₄ alkoxy, and NR_(c)R_(d)        wherein R_(c) and R_(d) are independently H or C₁₋₃ alkyl,        provided that R₃ and R₄ are not both H; and    -   n is 1 or 2;        or a pharmaceutically acceptable salt thereof.

Compounds of the present invention can also be selected from:

-   Acetic acid,    [4-[[2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]-,-   Acetic acid,    [4-[[(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]-,    and-   Acetic acid,    [4-[[(2S)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]-.

Specifically, compounds of the present invention further include:

-   {2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-pentylsulfanyl]-phenoxy}-acetic    acid;-   {4-[4-Cyano-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   (R)-{4-[2-Allyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   (R)-{-4-[2-Methoxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {-4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {3-Chloro-4-[2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenyl}-acetic    acid;-   {4-[2-Ethoxymethyl-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[4-Ethoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[2-(5-Chloro-thiophen-2-ylmethoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyano-2-(4-trifluoromethyl-phenoxymethyl)-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[5-Cyano-2-(4-trifluoromethyl-phenoxymethyl)-pent-4-enylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {3-Chloro-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenyl}-acetic    acid;-   {2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-2-(4-trifluoromethyl-phenoxymethyl)-propylsulfanyl]-phenoxy}-acetic    acid;-   {4-[2-Benzyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[2-(4-Butyryl-phenoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-propenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[2-methylsulfanylmethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-phenoxy}-acetic    acid;-   {4-[2,4-Diethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-but-3-enylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[2-(4-Trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-heptylsulfanyl]-phenoxy}-acetic    acid;-   {4-[4-Methoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyran-2-ylmethylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[4-(4-trifluoromethyl-phenyl)-but-3-enylsulfanyl]-phenoxy}-acetic    acid;-   (R)-{4-[2-Ethoxy-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   (R)-{4-[3-(4-Chloro-phenoxy)-2-ethoxy-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   (R)-{4-[3-(4-tert-Butyl-phenoxy)-2-ethoxy-propylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   (R)-{2-Methyl-4-[2-(4-trifluoromethoxy-phenoxymethyl)-butylsulfanyl]-phenoxy}-acetic    acid;-   (R)-{4-[2-(4-Chloro-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   (R)-{4-[2-(4-tert-Butyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   (R)-{3-Chloro-4-[2-ethoxy-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-phenyl}-acetic    acid;-   (R)-{3-Chloro-4-[3-(4-chloro-phenoxy)-2-ethoxy-propylsulfanyl]-phenyl}-acetic    acid;-   (R)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenylsulfanyl}-acetic    acid;-   (R)-{-4-[2-Ethoxy-3-(4-trifluoromethoxy-phenoxy)-propylsulfanyl]-2-methyl-phenylsulfanyl}-acetic    acid;-   (R)-{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenylsulfanyl}-acetic    acid;-   (R)-{2-Methyl-4-[2-(4-trifluoromethoxy-phenoxymethyl)-butylsulfanyl]-phenylsulfanyl}-acetic    acid;-   Acetic acid,    {4-(2R)-2-hydroxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl}-2-methyl-phenoxyy;-   Acetic acid,    {4-[(2S)-2-hydroxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-;    and-   {-4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propoxy]-2-methyl-phenoxy}-acetic    acid.

The present invention also provides compositions containing and methodsof using compounds of Formula (I). In particular, the present inventionprovides compositions containing and methods of using compounds ofFormula (I) as exemplified above.

Examples of preferred compounds include those described in Table 1below.

TABLE 1 Compound Number Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

The invention provides the disclosed compounds and closely related,pharmaceutically acceptable forms of the disclosed compounds, such assalts, esters, amides, hydrates or solvated forms thereof; masked orprotected forms; and racemic mixtures, or enantiomerically or opticallypure forms.

Pharmaceutically acceptable salts, esters, and amides includecarboxylate salts (e.g., C₁₋₈ alkyl, cycloalkyl, aryl, heteroaryl, ornon-aromatic heterocyclic) amino acid addition salts, esters, and amideswhich are within a reasonable benefit/risk ratio, pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. Representative saltsinclude hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate. These may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylamine, trimethylamine, andethylamine. See example, S. M. Berge, et al., ‘Pharmaceutical Salts,’ J.Pharm. Sci., 1977, 66:1-19, which is incorporated herein by reference.Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di (C₁₋₆ alkyl) amines. Secondary amines include 5-or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃ alkylprimary amines, and di (C₁₋₂ alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇ alkyl,C₅₋₇ cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl esters.

The invention also includes disclosed compounds having one or morefunctional groups (e.g., amino, or carboxyl) masked by a protectinggroup. Some of these masked or protected compounds are pharmaceuticallyacceptable; others will be useful as intermediates. Syntheticintermediates and processes disclosed herein, and minor modificationsthereof, are also within the scope of the invention.

Hydroxyl Protecting Groups

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate)

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyldithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Amino Protecting Gro ups

Protection for the amino group includes carbamates, amides, and special—NH protective groups.

Examples of carbamates include methyl and ethyl carbamates, substitutedethyl carbamates, assisted cleavage carbamates, photolytic cleavagecarbamates, urea-type derivatives, and miscellaneous carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,and 4-methoxyphenacyl.

Substituted Ethyl

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′-and 4′-pyridyl)ethyl,2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted Cleavage

Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic Cleavage

Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

Urea-Type Derivatives

Examples of urea-type derivatives include phenothiazinyl-(10)-carbonylderivative, N′-p-toluenesulfonylaminocarbonyl, andN′-phenylaminothiocarbonyl.

Miscellaneous Carbamates

Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

Examples of amides include:

Amides

N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-p-phenylbenzoyl.

Assisted Cleavage

N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

Cyclic Imide Derivatives

N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-pyridonyl.

Special—NH Protective Groups

Examples of special NH protective groups include

N-Alkyl and N-Aryl Amines

N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl,N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

Imine Derivatives

N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene,N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, andN—(N′,N′-dimethylaminomethylene).

Protection for the Carboxyl Group

Esters

Examples of esters include formate, benzoylformate, acetate,trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, benzoate.

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

2-Substituted Ethyl Esters

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl,2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(p-toluenesulfonyl)ethyl, 2-(2′-pyridyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl,cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

Substituted Benzyl Esters

Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

Silyl Esters

Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl anddi-t-butylmethylsilyl.

Activated Esters

Examples of activated esters include thiols.

Miscellaneous Derivatives

Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaminocobalt(III) complex.

Stannyl Esters

Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

C. Synthesis

The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Schemes 1 through 3 describe suggestedsynthetic routes. Using these Schemes, the guidelines below, and theexamples, a person of skill in the art may develop analogous or similarmethods for a given compound that are within the invention. Thesemethods are representative of the preferred synthetic schemes, but arenot to be construed as limiting the scope of the invention.

One skilled in the art will recognize that synthesis of the compounds ofthe present invention may be effected by purchasing an intermediate orprotected intermediate compounds described in any of the schemesdisclosed herein. One skilled in the art will further recognize thatduring any of the processes for preparation of the compounds in thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in ‘Protective Groups in Organic Synthesis’, John Wiley &Sons, 1991. These protecting groups may be removed at a convenient stageusing methods known from the art.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their components enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation. The compounds mayalso be resolved by formation of diastereomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column.

Examples of the described synthetic routes include Examples 1 through 9.Compounds analogous to the target compounds of these examples can bemade according to similar routes. The disclosed compounds are useful inbasic research and as pharmaceutical agents as described in the nextsection.

General Guidance

A preferred synthesis of Formula (I) is demonstrated in Schemes 1-9.

Abbreviations or acronyms useful herein include: AcOH (glacial aceticacid); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,2-dichloroethane); DIC(2-dimethylaminoisopropyl chloride hydrochloride); DIEA(diisopropylethylamine); DMAP (4-(dimethylamino)pyridine); DMF(dimethylformamide); EDC(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide); EtOAc (ethyl acetate);LAH (lithium aluminum hydride); mCPBA (3-chloroperoxybenzoic acid); NMI(1-methylimidazole); TEA (triethylamine);TFA (trifluoroacetic acid); THF(tetrahydrofuran);TMEDA (N,N,N′,N′-tetramethyl-ethylenediamine).

In accordance with Scheme 1, phenol 1-A, a variety of which arecommercially available (such as 3-methylphenol, 2-ethylphenol,2-propylphenol, 2,3-dimethylphenol, 2-chlorophenol, 2,3-dichlorophenol,2-bromophenol, and 2-aminophenol), is alkylated to form phenoxyaceticacid ethyl ester 1-B with a suitable haloacetic acid ester such asbromoacetic acid ethyl ester, in the presence of an appropriate basesuch as Cs₂CO₃, K₂CO₃, or NaH, in a suitable solvent such as CH₃CN orTHF. Sulfonation of the phenoxyacetic acid ethyl ester 1-B with anappropriate sulfonating agent, such as chlorosulfonic acid, occursselectively at the para position to provide4-chlorosulfonylphenoxyacetic acid ethyl ester 1-C. Transformation ofthe sulfonylchloride 1-C to benzenethiol 1-D is accomplished using ametal as a reducing agent, such as tin or zinc, in an acidic medium suchas ethanol or dioxane.

In Scheme 2, R₅ substituted diethyl malonate 2-A is reduced topropane-1,3-diol 2-B by using a suitable reducing agent such as lithiumaluminum hydride or diisobutylaluminum hydride. Mitsunobu reaction of2-B with phenol 2-C provides compound 2-D by employing atriarylphosphine such as triphenylphosphine, and an azodicarbonylreagent such as diisopropyl azodicarboxylate, in a suitable solvent suchas THF. Phenoxyacetic acid ethyl ester 2-E is obtained in two steps: (1)conversion of the alcohol 2-D to mesylate under standard conditions byemploying methanesulfonyl chloride and triethylamine in an appropriatesolvent such as CH₂Cl₂, and (2) alkylation of benzenethiol 1-D, preparedaccording to Scheme 1 above, with the mesylate intermediate using asuitable base such as Cs₂CO₃, K₂CO₃, or NaH, in an appropriate solventsuch as CH₃CN or THF, under nitrogen. Under standard saponificationconditions phenoxyacetic acid ethyl ester 2-E is converted to acid Iaunder nitrogen. The preferred hydrolysis conditions include using NaOHas a base in an aqueous alcoholic solvent system such as water-methanol,or using LiOH as a base in a milder water-THF system.

In Scheme 3, enantiomerically pure phenylacetic acid 3-A, a variety ofwhich are commercially available (such as (S)-(+)-2-phenylpropionicacid, (R)-(−)-2-phenylpropionic acid, (S)-(+)-2-phenylbutyric acid,(R)-(−)-2-phenylbutyric acid, (+)-3-methyl-2-phenylbutyric acid,(S)-(+)-2-phenylsuccinic acid, and (R)-(−)-2-phenylsuccinic acid), isreduced to alcohol by using borane and the alcohol is subsequentlyprotected as an acetate 3-B under standard conditions known in arts.Oxydation of the phenyl group in 3-B to acid 3-C is accomplished byemploying catalytic amount of ruthenium chloride and a large excess ofsodium periodate in a mixed solvent system such as CH₃CN—CCl₄-H₂O. Acid3-C is converted to alcohol 3-E in four steps: (1) methylation of acid3-C using (trimethysilyl)diazomethane as a methylating agent, (2) and(3) exchanging of the hydroxyl protecting group from acetate in 3-C totert-butyldimethyl silyloxy in 3-E under conventional conditions wellknown in arts, and (4) reduction of methyl ester by using an appropriatereducing agent such as diisobutylaluminum hydride.

Phenoxyacetic acid ethyl ester 3-F is obtained in two steps: (1)conversion of the alcohol 3-E to mesylate under standard conditions byemploying methanesulfonyl chloride and triethylamine in an appropriatesolvent such as CH₂Cl₂, and (2) alkylation of benzenethiol 1-D, preparedaccording to Scheme 1 above, with the mesylate intermediate using asuitable base such as Cs₂CO₃, K₂CO₃, or NaH, in an appropriate solventsuch as CH₃CN or THF, under nitrogen. After revealing of the hydroxylgroup by removal of the tert-butyldimethyl silyloxy group in 3-F,alcohol 3-G is transformed to 3-H by reacting with phenol 2-C underMitsunobu conditions. The preferred conditions include using atriarylphosphine such as triphenylphosphine, and an azodicarbonylreagent such as diisopropyl azodicarboxylate, in a suitable solvent suchas THF. Under standard saponification conditions phenoxyacetic acidethyl ester 3-His converted to acid Ia1 under nitrogen. The preferredhydrolysis conditions include using NaOH as a base in an aqueousalcoholic solvent system such as water-methanol, or using LiOH as a basein a milder water-THF system.

In Scheme 4, benzenethiol 1-D is dimerized to phenyl disulfide 4-A inthe presence of an appropriate oxidizing agent such as barium manganate.

Mitsunobu reaction of 2-hydroxymethylpropane-1,3-diol 4-B with phenol2-C provides compound 4-C by employing a triarylphosphine such astriphenylphosphine, and an azodicarbonyl reagent such as diisopropylazodicarboxylate, in a suitable solvent such as THF. The formation ofcarbon-sulfur bond in compound 4-D is carried out by Mitsunobu reactionof diol 4-C with phenyl disulfide 4-A by using tri-n-butylphosphine andpyridine. The third Mitsunobu reaction of 4-D with acetone cyanohydrinconverted the alcohol 4-D to the cyano compound 4-E under standardMitsunobu reaction conditions. As usual, basic hydrolysis ofphenoxyacetic acid ethyl ester 4-E affords acid 1a2.

As shown in Scheme 5, wherein R is alkyl or aryl, alkyl ether compound5-A could be prepared by alkylation of alcohol 4-D, an intermediateprepared in Scheme 4 above, with a variety of alkylating agents such asalkyl trifluoromethanesulfonates or alkyl halides in the presence of asuitable base such as sodium hydride or sodium bis(trimethylsilyl)amide.Similarly, aryl ether could be synthesized by Mitsunobu reaction of 4-Dwith many different substituted phenols available. Finally,saponification of ethyl ester 5-A under standard conditions gives acidIa3.

In accordance with Scheme 6, Mitsunobu reaction of (R)-(+)-glycidol, or(S)-(−)-glycidol, or racemic glycidol 6-A with phenol 2-C providesepoxide 6-B by employing a triarylphosphine such as triphenylphosphine,and an azodicarbonyl reagent such as diisopropyl azodicarboxylate, in asuitable solvent such as THF. Epoxide ring opening of 6-B withbenzenethiol 1-D in the presence of a catalytic amount oftetrabutylammonium fluoride furnishes alcohol 6-C. Alkyl ether compound6-D could be prepared by alkylation of alcohol 6-C with a variety ofalkylating agents such as alkyl trifluoromethanesulfonates or alkylhalides in the presence of a suitable base such as sodium hydride orsodium bis(trimethylsilyl)amide in a suitable solvent such as THF orDMF. Similarly, aryl ether 6-D could be synthesized by Mitsunobureaction of 6-C with many different substituted phenols available byusing triphenylphosphine and an appropriate azodicarbonyl reagent suchas 1,1′-(azodicarbonyl)dipiperidine or diethyl azodicarboxylate.Finally, saponification of ethyl ester 6-D under standard conditionsgives acid 1a4.

In accordance with Scheme 7, (4-hydroxyphenyl)acetic acid 7-A, a varietyof which are commercially available (such as 3-bromo-4-hydroxyphenylacetic acid, 3-chloro-4-hydroxyphenyl acetic acid,3-fluoro-4-hydroxyphenyl acetic acid, 4-hydroxy-3-methoxyphenyl aceticacid, and 4-hydroxy-3-nitrophenyl acetic acid), is methylated to form(4-hydroxyphenyl)acetic acid methyl ester 7-B in methanol in thepresence of a catalytic amount of a suitable acid such as sulfuric acidor hydrochloric acid. The phenol 7-B is converted to(4-dimethylthiocarbamoyloxyphenyl)acetic acid methyl ester 7-C byreacting with dimethylthiocarbamoyl chloride in the presence of someappropriate bases such as triethylamine and 4-(dimethylamino)pyridine.At high temperature, in the preferred range of 250 to 300° C., 7-C isrearranged to (4-dimethylcarbamoylsulfanylphenyl)acetic acid methylester 7-D in a high boiling point solvent such as tetradecane. Bytreatment with a suitable base such as sodium methoxide 7-D istransformed to (4-mercaptophenyl)acetic acid methyl ester 7-E.

In accordance with Scheme 8, wherein R is alkyl, epoxide 8-B is obtainedby treatment of phenol 2-C with an appropriate base such as cesiumcarbonate followed by alkylation with 2-chloromethyl-oxirane 8-A.Epoxide ring opening of 8-B with benzenethiol 7-E, prepared in Scheme 7above, in the presence of a catalytic amount of tetrabutylammoniumfluoride furnishes alcohol 8-C. Alkyl ether compound 8-D could beprepared by alkylation of alcohol 8-C with a variety of alkylatingagents such as alkyl trifluoromethanesulfonates or alkyl halides in thepresence of a suitable base such as sodium hydride or sodiumbis(trimethylsilyl)amide in a suitable solvent such as THF or DMF.Finally, saponification of methyl ester 8-D under standard conditionsgives acid Ib1.

In Scheme 9, wherein R is as shown above, aldehyde 9-B could be preparedin two steps by methylation of acid 9-A using(trimethysilyl)diazomethane as a methylating agent followed by reductionof the methyl ester intermediate with a suitable reducing agent such asdiisobutylaluminum hydride. Aldehyde 9-B is transformed to epoxide 9-Cby reacting with dimethylsulfonium methylide, which is generated in-situfrom treatment of trimethylsulfonium iodide with a strong base such asDMSO anion. Epoxide ring opening of 9-C with benzenethiol 1-D in thepresence of a catalytic amount of tetrabutylammonium fluoride furnishesalcohol 9-D. Alkyl ether compound 9-E could be prepared by alkylation ofalcohol 9-D with a variety of alkylating agents such as alkyltrifluoromethanesulfonates or alkyl halides in the presence of asuitable base such as sodium hydride or sodium bis(trimethylsilyl)amidein a suitable solvent such as THF or DMF. Finally, saponification ofethyl ester 9-E under standard conditions gives acid Ic1.

EXAMPLES Example A

{2-Methyl-4-[2-methyl-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-aceticacid

According to Scheme A1, to a flask containing chlorosulfonic acid (15.0mL, 226 mmol) at 4° C. was added ethyl (2-methylphenoxy)acetate A1 a(10.0 g, 51.6 mmol) slowly. The mixture was stirred at 4° C. for 30 minand room temperature for 2 h, and then poured into ice water. Theprecipitated white solid was filtered, washed with water, and driedunder vacuum overnight to provide 14.0 g (93%) of A1b as a white solid;1H NMR (300 MHz, CDCl₃) δ 7.87-7.84 (m, 2 H), 6.80 (d, J=9.5 Hz, 1 H),4.76 (s, 2 H), 4.29 (q, J=7.1 Hz, 2 H), 2.37 (s, 3 H), 1.31 (t, J=7.1Hz, 3 H); MS (ES) m/z: 315 (M+Na+).

To a solution of A1b (4.70 g, 16.1 mmol) in EtOH (20 mL) was added asolution of 4.0 M HCl in dioxane (20 mL) followed by 100 mesh tin powder(9.80 g, 82.6 mmol) portionwise. The mixture was refluxed for 2 h,poured into CH₂Cl₂/ice (100 mL), and filtered. The filtrate wasseparated, and the aqueous layer was extracted with CH₂Cl₂. The combinedorganic phases were washed with water, dried, and concentrated to give3.56 g (98%) of A1c as a yellow oil; 1H NMR (300 MHz, CDCl₃) δ 7.14-7.03(m, 2 H), 6.59 (d, J=8.4 Hz, 1 H), 4.60 (s, 2 H), 4.25 (q, J=7.1 Hz, 2H), 2.24 (s, 3 H), 1.29 (t, J=7.1 Hz, 3 H).

According to Scheme A2, to a suspension of lithium aluminum hydride (152mg, 4.00 mmol) in THF (3 mL) at 0° C. was added diethyl methylmalonateA2a (348 mg, 2.00 mmol) dropwise. The reaction mixture was stirred atroom temperature for 1.5 h, quenched with water (0.2 mL) and 5 N NaOH(0.2 mL), and further diluted with water (0.6 mL). After stirring for 20min, the precipitated solid was filtered through Celite and washed withMeOH/CH₂Cl₂. The filtrate was dried, concentrated, and purified bycolumn chromatography to give 135 mg (75%) of A2b; 1H NMR (300 MHz,CDCl₃) δ 3.68 (dd, J=10.7, 4.5 Hz, 2 H), 3.58 (dd, J=10.7, 7.6 Hz, 2 H),3.50 (s, 2 H), 1.96-1.89 (m, 1 H), 0.86 (d, J=7.0 Hz, 3 H); MS (ES) m/z:113 (M+Na+).

To a mixture of A2b (113 mg, 1.26 mmol), trifluoromethylphenol (156 mg,0.963 mmol), and triphenylphosphine (252 mg, 0.962 mmol) in THF (3 mL)at 0° C. was added diisopropyl azodicarboxylate (195 mg, 0.965 mmol).The mixture was stirred at room temperature overnight and concentrated.The residue was purified by column chromatography to provide 149 mg(51%) of A2c; 1H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=8.8 Hz, 2 H), 6.96(d, J=8.7 Hz, 2 H), 3.98 (m, 2 H), 3.71 (m, 2 H), 2.24-2.16 (m, 1 H),1.80 (s, 1 H), 1.05 (d, J=7.0 Hz, 3 H); MS (ES) m/z: 235 (M+H+).

General Procedure 1 for the Formation of Thioether:

To a solution of A2c (135 mg, 0.577 mmol) in CH₂Cl₂ (3 mL) at 0° C. wereadded Et₃N (0.162 mL, 1.16 mmol) and methanesulfonyl chloride (93 mg,0.81 mmol). The mixture was stirred at 0° C. for 30 min and roomtemperature for 1 h and diluted with saturated NaHCO₃. The organic layerwas separated and the aqueous layer was extracted with CH₂Cl₂ (×3). Thecombined organic phases were dried and concentrated to provide themesylate.

A mixture of the above mesylate, (4-mercapto-2-methyl-phenoxy)aceticacid ethyl ester A1c (197 mg, 0.872 mmol), and Cs₂CO₃ (472 mg, 1.45mmol) in CH₃CN (5 mL) was stirred at room temperature for 3 h. Water wasadded and the mixture was extracted with Et₂O. The combined organiclayers were dried, concentrated, and column chromatographed(EtOAc/hexane:1/10) to provide 187 mg (73%, two steps) of A2d; 1H NMR(300 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.20 (d, J=1.7 Hz, 1 H),7.15 (dd, J=8.4, 2.2 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2 H), 6.57 (d, J=8.4Hz, 1 H), 4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 3.94 (dd, J=5.7, 2.7Hz, 2 H), 3.04 (dd, J=13.6, 6.6 Hz, 1 H), 2.86 (dd, J=13.3, 6.5 Hz, 1H), 2.24-2.16 (m, 1 H), 2.23 (s, 3 H), 1.29 (t, J=7.1 Hz, 3 H), 1.14 (d,J=6.8 Hz, 3 H); MS (ES) m/z: 465 (M+Na+).

General Procedure 2 for the Hydrolysis of the Ethyl and Methyl Esters:

To a solution of A2d (130 mg, 0.294 mmol) in THF (2 mL) under N₂ wasadded 1.0 M LiOH (0.58 mL, 0.58 mmol). The mixture was stirred for 2 h,acidified with 1 M HCl, and extracted with EtOAc (×3). The extracts weredried, concentrated, and purified by column chromatography (CH₂Cl₂/MeOH:10/1) to give 109 mg (90%) of Compound 1; 1H NMR (400 MHz, CDCl₃) δ 7.50(d, J=8.7 Hz, 2 H), 7.18 (s, 1 H), 7.14 (d, J=8.4 Hz, 1 H), 6.88 (d,J=8.7 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H), 4.57 (s, 2 H), 3.92 (d, J=5.6Hz, 2 H), 3.04 (dd, J=13.3, 6.5 Hz, 1 H), 2.85 (dd, J=13.2, 6.5 Hz, 1H), 2.24-2.15 (m, 1 H), 2.19 (s, 3 H), 1.13 (d, J=6.8 Hz, 3 H); MS (ES)m/z: 415 (M+H+).

Example B

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenoxy}-aceticacid

To a solution of (S)-(+)-2-phenylbutyric acid B1 (352 mg, 2.14 mmol) inTHF (3 mL) at 0° C. was slowly added a solution of 1.0 M BH₃.THF complexin THF (2.14 mL, 2.14 mmol). The mixture was allowed to warm up to roomtemperature, stirred at room temperature overnight, quenched with waterand followed by 1.0 N HCl, and extracted with Et₂O (×3). The extractswere dried, concentrated, and column chromatographed to give 283 mg(88%) of B2; 1H NMR (300 MHz, CDCl₃) δ 7.34-7.29 (m, 2 H), 7.24-7.16 (m,3 H), 3.70 (m, 2 H), 2.65 (m, 1 H), 1.79-1.67 (m, 1 H), 1.63-1.48 (m, 2H), 0.82 (t, J=7.4 Hz, 3 H); MS (ES) m/z: 173 (M+Na+).

To a mixture of B2 (283 mg, 1.88 mmol), pyridine (0.76 mL, 9.4 mmol),and DMAP (23 mg, 0.19 mmol) in CH₂Cl₂ (3 mL) at 0° C. was added acetylchloride (369 mg, 4.70 mmol). The mixture was stirred at roomtemperature for 2 h, diluted with 1.0 N HCl, and extracted with CH₂Cl₂.The combined organic phases were washed with 1.0 N HCl (×3) and brine,dried, concentrated, and column chromatographed to provide 343 mg (95%)of B3; 1H NMR (300 MHz, CDCl₃) δ 7.33-7.28 (m, 2 H), 7.25-7.17 (m, 3 H),4.21 (m, 2 H), 2.86-2.77 (m, 1 H), 1.98 (s, 3 H), 1.86-1.73 (m, 1 H),1.68-1.53 (m, 1 H), 0.82 (t, J=7.4 Hz, 3 H); MS (ES) m/z: 215 (M+Na+).

To a solution of B3 (160 mg, 0.833 mmol) in a mixture solvents of CCl₄(2 mL), CH₃CN (2 mL), and water (3 mL) were added NalO₄ (3.55 g, 16.6mmol) and RuCl₃ (12 mg, 0.058 mmol). After stirring at room temperatureovernight, the mixture was partitioned between water and CH₂Cl₂. Thecombined organic layers were dried, filtered, and concentrated. Theresidue was redissolved in Et₂O and filtered through Celite. Thefiltrate was dried and column chromatographed (CH₂Cl₂/MeOH: 9/1) to give97 mg (73%) of B4; 1H NMR (300 MHz, CDCl₃) δ 4.24 (d, J=6.7 Hz, 2 H),2.67 (m, 1 H), 2.06 (s, 3 H), 1.77-1.56 (m, 2 H), 1.00 (t, J=7.5 Hz, 3H); MS (ES) m/z: 183 (M+Na+).

To a solution of B4 (218 mg, 1.36 mmol) in Et₂O (4 mL) and MeOH (2 mL)was added 2.0 M TMSCHN₂ (2.08 mL, 4.16 mmol) in Et₂O slowly. Afterstirring at room temperature for 3 h, the solvents were removed underreduced pressure to give the methyl ester. To the dissolved residue inMeOH (2 mL) was added K₂CO₃ (188 mg, 1.36 mmol) and the resulted mixturewas stirred for 20 min. After removal of solvent at low temperature, theresidue was partitioned between Et₂O and water. The organic layer wasdried, concentrated, and column chromatographed (EtOAc/hexane:1/2) toafford 176 mg (98%) of B5; 1H NMR (300 MHz, CDCl₃) δ 3.82-3.73 (m, 2 H),3.73 (s, 3 H), 2.53 (m, 1 H), 2.41 (brs, 1 H), 1.73-1.55 (m, 2 H), 0.95(t, J=7.5 Hz, 3 H); MS (ES) m/z: 155 (M+Na+).

A mixture of B5 (225 mg, 1.70 mmol), tert-butyldimethylsilyl chloride(334 mg, 2.22 mmol), and imidazole (290 mg, 4.26 mmol) in DMF (1.7 mL)was stirred for 14 h and partitioned between water and Et₂O. The organiclayer was dried, concentrated, and column chromatographed to provide 385mg (92%) of B6; 1H NMR (400 MHz, CDCl₃) δ 3.77 (dd, J=9.7, 7.8 Hz, 1 H),3.70-3.66 (m, 1 H), 3.68 (s, 3 H), 2.52 (m, 1 H), 1.64-1.51 (m, 2 H),0.91 (t, J=7.5 Hz, 3 H), 0.87 (s, 9 H), 0.03 (s, 6 H); MS (ES) m/z: 269(M+Na+).

To a solution of B6 (350 mg, 1.42 mmol) in CH₂Cl₂ (5 mL) at −78° C. wasadded 1.0 M DIBAL-H (3.55 mL, 3.55 mmol) dropwise. After stirring at−78° C. for 15 min, the mixture was allowed to gradually warm up to 0°C., stirred at the same temperature for 10 min, quenched with MeOH.After stirring at room temperature for 1 h, the precipitated solid wasfiltered through Celite and washed with CH₂Cl₂/MeOH. The filtrate wasdried, concentrated, and column chromatographed to give 273 mg (88%) ofB7; 1H NMR (300 MHz, CDCl₃) δ 3.82 (dd, J=9.9, 4.0 Hz, 1 H), 3.75 (dd,J=11.0, 3.3 Hz, 1 H), 3.67-3.58 (m, 2 H), 2.78 (brs, 1 H), 1.68-1.61 (m,1 H), 1.33-1.23 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H), 0.90 (s, 9 H), 0.08(s, 6 H); MS (ES) m/z: 219 (M+H+).

B8 (61%) was prepared following general procedure 1 in Example A; 1H NMR(300 MHz, CDCl₃) δ 7.19 (d, J=1.8 Hz, 1 H), 7.15 (dd, J=8.4, 2.2 Hz, 1H), 6.62 (d, J=8.4 Hz, 1 H), 4.60 (s, 2 H), 4.26 (q, J=7.1 Hz, 2 H),3.67 (dd, J=10.0, 4.7 Hz, 1 H), 3.57 (dd, J=10.0, 5.5 Hz, 1 H), 2.97(dd, J=12.9, 6.8 Hz, 1 H), 2.79 (dd, J=12.9, 6.0 Hz, 1 H), 2.26 (s, 3H), 1.62-1.56 (m, 1 H), 1.44 (m, 2 H), 1.29 (t, J=7.1 Hz, 3 H), 0.88 (t,J=7.4 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H); MS (ES) m/z: 449 (M+Na+).

A solution of B8 (213 mg, 0.500 mmol) in CH₂Cl₂ (2 mL) was treated witha solution of 1.0 M tetrabutyl ammonium fluoride (1.50 mL, 1.50 mmol) inTHF for 3 h and partitioned between water and CH₂Cl₂. The organic layerwas dried, concentrated, and column chromatographed to provide 33 mg(21%) of B9; 1H NMR (300 MHz, CDCl₃) δ 7.22 (d, J=1.7 Hz, 1 H), 7.17(dd, J=8.4, 2.2 Hz, 1 H), 6.63 (d, J=8.4 Hz, 1 H), 4.61 (s, 2 H), 4.25(q, J=7.1 Hz, 2 H), 3.72 (dd, J=10.9, 4.7 Hz, 1 H), 3.64 (dd, J=11.0,5.8 Hz, 1 H), 2.92 (d, J=6.4 Hz, 2 H), 2.26 (s, 3 H), 1.73-1.63 (m, 2H),1.45 (m, 2 H), 1.29 (t, J=7.1 Hz, 3 H), 0.91 (t, J=7.4 Hz, 3 H); MS (ES)m/z: 335 (M+Na+).

To a mixture of B9 (120 mg, 0.385 mmol), trifluoromethylphenol (93 mg,0.57 mmol), and triphenylphosphine (150 mg, 0.573 mmol) in THF (3 mL) at0° C. was added diisopropyl azodicarboxylate (115 mg, 0.569 mmol). Themixture was stirred at room temperature overnight and concentrated. Theresidue was purified by column chromatography twice (EtOAc/hexane:1/10;CH₂Cl₂/hexane: 2/1) to provide 121 mg (69%) of B10; 1H NMR (300 MHz,CDCl₃) δ 7.51 (d, J=8.7 Hz, 2 H), 7.19 (d, J=1.8 Hz, 1 H), 7.15 (dd,J=8.4, 2.3 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2 H), 6.56 (d, J=8.4 Hz, 1 H),4.56 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.01 (m, 2 H), 3.00 (d, J=6.4Hz, 2 H), 2.21 (s, 3 H), 1.96 (m, 1 H), 1.59 (m, 2 H), 1.28 (t, J=7.1Hz, 3 H), 0.94 (t, J=7.4 Hz, 3 H); MS (ES) m/z: 479 (M+Na+).

Compound 2 (88%) was prepared following general procedure 2 in ExampleA; 1H NMR (400 MHz, CDCl₃) δ 7.49 (d, J=8.6 Hz, 2 H), 7.15 (s, 1 H),7.11 (d, J=8.3 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2 H), 6.53 (d, J=8.2 Hz, 1H), 4.50 (s, 2 H), 4.03-3.95 (m, 2 H), 3.00-2.98 (m, 2 H), 2.16 (s, 3H), 1.95 (m, 1 H), 1.57 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H); MS (ES) m/z:429 (M+H+).

Example C

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenoxy}-aceticacid

To a suspension of lithium aluminum hydride (101 mg, 2.66 mmol) in THF(3 mL) at 0° C. was added diethyl ethylmalonate C1 (250 mg, 1.33 mmol)dropwise. The reaction mixture was stirred at room temperature for 2 h,quenched with water (0.1 mL) and 5 N NaOH (0.2 mL), diluted with water(0.6 mL), filtered through Celite, and washed the solid withMeOH/CH₂Cl₂. The filtrate was dried, concentrated, and purified bycolumn chromatography to give 110 mg (80%) of C2; 1H NMR (300 MHz,CDCl₃) δ 3.79 (dd, J=10.7, 3.9 Hz, 2 H), 3.64 (dd, J=10.7, 7.5 Hz, 2 H),3.27 (s, 2 H), 1.67 (m, 1 H), 1.29 (m, 2 H), 0.94 (t, J=7.5 Hz, 3 H); MS(ES) m/z: 127 (M+Na+).

To a mixture of C2 (108 mg, 1.04 mmol), trifluoromethylphenol (130 mg,0.802 mmol), and triphenylphosphine (210 mg, 0.802 mmol) in THF (3 mL)at 0° C. was added diisopropyl azodicarboxylate (162 mg, 0.802 mmol).The mixture was stirred at room temperature overnight, diluted withwater, and extracted with Et₂O (×3). The extracts were dried,concentrated, and column chromatographed to provide 134 mg (52%) of C3;1H NMR (400 MHz, CDCl₃) δ 7.54 (d, J=8.8 Hz, 2 H), 6.97 (d, J=8.8 Hz, 2H), 4.05 (m, 2 H), 3.80 (dd, J=10.8, 4.4 Hz, 1 H), 3.74 (dd, J=10.8, 6.5Hz, 1 H), 1.94 (m, 1 H), 1.50 (m, 2 H), 1.00 (t, J=7.5 Hz, 3 H); MS (ES)m/z: 249 (M+Na+).

C4 (81%) was prepared following general procedure 1 in Example A; 1H NMR(300 MHz, CDCl₃) δ 7.50 (d, J=8.6 Hz, 2 H), 7.19 (d, J=1.8 Hz, 1 H),7.15 (dd, J=8.4, 2.2 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2 H), 6.56 (d, J=8.4Hz, 1 H), 4.56 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.01 (m, 2 H), 3.00(d, J=6.4 Hz, 2 H), 2.21 (s, 3 H), 1.96 (m, 1 H), 1.59 (m, 2 H), 1.28(t, J=7.1 Hz, 3 H), 0.94 (t, J=7.5 Hz, 3 H); MS (ES) m/z: 479 (M+Na+).Anal. Calcd for C₂₃H₂₇F₃O₄S: C, 60.51; H, 5.96. Found: C, 60.69; H,5.56.

Compound 3 (92%) was prepared following general procedure 2 in ExampleA; 1H NMR (300 MHz, MeOH-d4) δ 7.53 (d, J=8.6 Hz, 2 H), 7.18 (s, 1 H),7.15 (m, 1 H), 6.96 (d, J=8.6 Hz, 2 H), 6.66 (d, J=8.1 Hz, 1 H), 4.55(s, 2 H), 4.04 (m, 2 H), 3.00 (d, J=6.3 Hz, 2 H), 2.16 (s, 3 H), 1.92(m, 1 H), 1.58 (m, 2 H), 0.94 (t, J=7.5 Hz, 3 H); MS (ES) m/z: 451(M+Na+).

Example D

{4-[2-(4-Trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenoxy}-aceticacid

Replacing (4-mercapto-2-methyl-phenoxy)acetic acid ethyl ester A1c with4-mercapto-phenol and following general procedure 1 in Example A gave D1(28%); 1H NMR (300 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.28 (d, J=8.7Hz, 2 H), 6.91 (d, J=8.6 Hz, 2 H), 6.72 (d, J=8.7 Hz, 2 H), 4.84 (s, 1H), 4.02 (dd, J=5.2, 3.8 Hz, 2 H), 2.99 (d, J=6.0 Hz, 2 H), 1.95 (m, 1H), 1.59 (m, 2 H), 0.94 (t, J=7.5 Hz, 3 H); MS (ES) m/z: 357 (M+H+).

A mixture of D1 (86 mg, 0.24 mmol), bromoacetic acid methyl ester (55mg, 0.36 mmol), and Cs₂CO₃ (157 mg, 0.482 mmol) in CH₃CN (2 mL) wasstirred for 2 h and partitioned between Et₂O and water. The organiclayer was dried, concentrated, and column chromatographed(EtOAc/hexane:1/6) to give 99 mg (96%) of the methyl ester. Followinggeneral procedure 2, the above methyl ester was converted to acidCompound 4 (89%); 1H NMR (300 MHz, CDCl₃) δ 8.91 (brs, 1 H), 7.49 (d,J=8.7 Hz, 2 H), 7.26 (d, J=8.3 Hz, 2 H), 6.88 (d, J=8.6 Hz, 2 H), 6.74(d, J=8.5 Hz, 2 H), 4.46 (s, 2 H), 3.98 (m, 2 H), 3.01-2.92 (m, 2 H),1.93 (m, 1 H), 1.56 (m, 2 H), 0.92 (t, J=7.4 Hz, 3 H); MS (ES) m/z: 437(M+Na+).

Example E

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-pentylsulfanyl]-phenoxy}-aceticacid

To a solution of 1.0 M diisobutylaluminum hydride (50 mL, 50 mmol) inCH₂Cl₂ at −78° C. was added diethyl propylmalonate E1 (2.02 g, 10.0mmol). The reaction mixture was allowed to gradually warm to 0° C.,stirred at 0° C. for 30 min, and quenched with MeOH. The precipitatedsolid was filtered through Celite and washed with MeOH/CH₂Cl₂. Thefiltrate was concentrated and purified by column chromatography (EtOAc)to give 709 mg (60%) of E2; 1H NMR (300 MHz, CDCl₃) δ 3.80 (dd, J=10.7,3.8 Hz, 2 H), 3.63 (dd, J=10.7, 7.7 Hz, 2 H), 2.82 (s, 2 H), 1.84-1.71(m, 1 H), 1.42-1.28 (m, 2 H), 1.24-1.17 (m, 2 H), 0.91 (t, J=7.2 Hz, 3H); MS (ES) m/z: 141 (M+Na+).

To a solution of E2 (300 mg, 2.54 mmol) in CH₂Cl₂ (5 mL) at 0° C. wereadded Et₃N (1.06 mL, 7.62 mmol) and methanesulfonyl chloride (729 mg,6.36 mmol). The mixture was stirred at 0° C. for 2 h and diluted withsaturated NaHCO₃. The organic layer was separated and the aqueous layerwas extracted with CH₂Cl₂ (×3). The combined organic phases were dried,concentrated, and column chromatographed (EtOAc/hexane:1/1) to provide655 mg (94%) of E3; 1H NMR (300 MHz, CDCl₃) δ 4.29 (dd, J=10.0, 4.3 Hz,2 H), 4.20 (dd, J=10.0, 6.4 Hz, 2 H), 3.05 (s, 6 H), 2.22-2.15 (m, 1 H),1.42 (m, 4 H), 0.97-0.93 (m, 3 H); MS (ES) m/z: 297 (M+Na+).

To a suspension of NaH (80 mg, 2.0 mmol; 60% in mineral oil) in THF (2mL) was added a solution of 4-trifluoromethylphenol (324 mg, 2.0 mmol)in THF (2 mL). After stirring at room temperature for 30 min, a solutionof E3 (659 mg, 2.40 mmol) in THF (3 mL) was added and the resultingmixture was refluxed for 6 h. Water was added and the mixture wasextracted with Et₂O. The extracts were dried, concentrated, and columnchromatographed (EtOAc/hexane:1/4) to afford 170 mg (25%) of E4; 1H NMR(300 MHz, CDCl₃) δ 7.54 (d, J=8.6 Hz, 2 H), 6.96 (d, J=8.6 Hz, 2 H),4.37 (dd, J=9.9, 4.9 Hz, 1 H), 4.32 (dd, J=9.9, 6.0 Hz, 1 H), 4.04 (dd,J=9.4, 4.6 Hz, 1 H), 3.98 (dd, J=9.3, 6.4 Hz, 1 H), 2.97 (s, 3 H), 2.25(m, 1 H), 1.53-1.39 (m, 4 H), 0.96 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 363(M+Na+).

General Procedure 3 for the Formation of Thioether:

To a solution of E4 (165 mg, 0.485 mmol) in CH₃CN (5 mL) was addedCs₂CO₃ (391 mg, 1.20 mmol) followed by a solution of(4-mercapto-2-methyl-phenoxy)acetic acid ethyl ester A1c (163 mg, 0.721mmol) in CH₃CN (3 mL). After stirring for 5 h at room temperature, waterwas added and the mixture was extracted with Et₂O. The combined organiclayers were dried, concentrated, and column chromatographed(EtOAc/hexane:1/10) to provide 158 mg (70%) of E5; 1H NMR (300 MHz,CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.19 (d, J=1.5 Hz, 1 H), 7.14 (dd,J=8.4, 2.3 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2 H), 6.55 (d, J=8.4 Hz, 1 H),4.56 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.03 (dd, J=9.3, 4.9 Hz, 1 H),3.97 (dd, J=9.2, 5.6 Hz, 1 H), 3.00 (d, J=6.5 Hz, 2H), 2.21 (s, 3 H),2.05 (m, 1 H), 1.57-1.48 (m, 2 H), 1.40-1.32 (m, 2 H), 1.29 (t, J=7.1Hz, 3 H), 0.91 (t, J=7.2 Hz, 3 H); MS (ES) m/z: 493 (M+Na+). Anal. Calcdfor C₂₄H₂₉F₃O₄S: C, 61.26; H, 6.21. Found: C, 61.49; H, 6.35.

Following general procedure 2 in Example A gave Compound 5 (94%); 1H NMR(400 MHz, CDCl₃) δ 7.50 (d, J=8.7 Hz, 2 H), 7.18 (d, J=1.7 Hz, 1 H),7.15 (dd, J=8.5, 2.0 Hz, 1 H), 6.88 (d, J=8.7 Hz, 2 H), 6.57 (d, J=8.4Hz, 1 H), 4.60 (s, 2 H), 4.02 (dd, J=9.2, 4.7 Hz, 1 H), 3.97 (dd, J=9.2,5.7 Hz, 1 H), 3.01 (m, 2 H), 2.19 (s, 3H), 2.05 (m, 1 H), 1.54-1.49 (m,2 H), 1.37 (m, 2 H), 0.91 (t, J=7.2 Hz, 3 H); MS (ES) m/z: 465 (M+Na+).Anal. Calcd for C₂₂H₂₅F₃O₄S: C, 59.72; H, 5.69. Found: C, 59.63; H,5.75.

Example F

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-heptylsulfanyl]-phenoxy}-aceticacid

To a suspension of lithium aluminum hydride (114 mg, 3.00 mmol) in THF(3 mL) at 0° C. was added 2-pentylmalonic acid diethyl ester F1 (346 mg,1.50 mmol) dropwise. The reaction mixture was stirred at roomtemperature for 2 h, quenched with water (0.1 mL) and 5 N NaOH (0.2 mL)at 0° C., and diluted with water (0.6 mL). The precipitated solid wasfiltered through Celite and washed with MeOH/CH₂Cl₂. The filtrate wasdried, concentrated, and purified by column chromatography(EtOAc/hexane:1/1) to give 181 mg (82%) of F2; 1H NMR (300 MHz, CDCl₃) δ3.79 (dd, J=10.7, 3.8 Hz, 2 H), 3.62 (dd, J=10.7, 7.7 Hz, 2 H), 3.16 (s,2 H), 1.75 (m, 1 H), 1.34-1.18 (m, 8 H), 0.88 (t, J=6.8 Hz, 3 H); MS(ES) m/z: 169 (M+Na+).

To a mixture of F2 (176 mg, 1.21 mmol), trifluoromethylphenol (292 mg,1.80 mmol), and triphenylphosphine (472 mg, 1.80 mmol) in THF (3 mL) at0° C. was added diisopropyl azodicarboxylate (195 mg, 1.80 mmol). Themixture was stirred at 0° C. for 30 min and then room temperature for 6h, diluted with water, and extracted with Et₂O. The extracts were dried,concentrated, and purified by column chromatography to provide 108 mg(31%) of F3; 1H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.6 Hz, 2 H), 6.96 (d,J=8.6 Hz, 2 H), 4.03 (m, 2 H), 3.75 (m, 2 H), 2.04-1.95 (m, 1 H),1.44-1.36 (m, 4 H), 1.31-1.25 (m, 4 H), 0.89 (t, J=6.8 Hz, 3 H); MS (ES)m/z: 313 (M+Na+).

Following general procedure 1 in Example A gave F4 (78%); 1H NMR (300MHz, CDCl₃) δ 7.50 (d, J=8.6 Hz, 2 H), 7.19 (d, J=1.7 Hz, 1 H), 7.14(dd, J=8.4, 2.2 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2 H), 6.55 (d, J=8.4 Hz, 1H), 4.56 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.00 (m, 2 H), 3.01 (d,J=6.8 Hz, 2 H), 2.21 (s, 3 H), 2.03 (m, 1 H), 1.56-1.49 (m, 2 H),1.37-1.22 (m, 6 H), 1.28 (t, J=7.1 Hz, 3 H), 0.87 (t, J=6.8 Hz, 3 H); MS(ES) m/z: 521 (M+Na+).

Following general procedure 2 in Example A gave Compound 6 (91%); 1H NMR(300 MHz, CDCl₃) δ 9.23 (brs, 1 H), 7.50 (d, J=8.7 Hz, 2 H), 7.19 (d,J=1.8 Hz, 1 H), 7.15 (dd, J=8.4, 2.2 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2 H),6.57 (d, J=8.4 Hz, 1 H), 4.61 (s, 2 H), 4.00 (m, 2 H), 3.03-3.00 (m, 2H), 2.20 (s, 3 H), 2.04 (m, 1 H), 1.56-1.49 (m, 2 H), 1.37-1.23 (m, 6H), 0.87 (t, J=6.8 Hz, 3 H); MS (ES) m/z: 493 (M+Na+).

Example G

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-aceticacid

To a mixture of 4-trifluoromethylphenol (1.00 g, 6.17 mmol) and Et₃N(871 mg, 8.63 mmol) in CH₂Cl₂ (20 mL) at 4° C. was added phenoxylacetylchloride (1.37 g, 7.42 mmol). After stirring for 2 h at roomtemperature, the white solid was filtered and washed with Et₂O. Thefiltrate was washed with water, dried, concentrated, and purified bycolumn chromatography to give 1.79 g (94%) of G1 as a white solid; 1HNMR (300 MHz, CDCl₃) δ 7.66 (d, J=8.7 Hz, 2 H), 7.43-7.33 (m, 5 H), 7.25(d, J=8.4 Hz, 2 H), 4.73 (s, 2 H), 4.37 (s, 2 H).

To a solution of G1 (1.20 g, 3.87 mmol) in THF (20 mL) at −78° C. wasintroduced a solution of 0.5 M Tebbe reagent (9.3 mL, 4.7 mmol) intoluene. The mixture was stirred at −78° C. to 2° C. for 2 h andquenched with water dropwise. The formed solid was filtered and washedwith Et₂O. The filtrate was concentrated and purified by columnchromatography to provide 890 mg (75%) of G2 as a clear oil; 1H NMR (300MHz, CDCl₃) δ 7.60 (d, J=8.5 Hz, 2 H), 7.36-7.29 (m, 5 H), 7.16 (d,J=8.6 Hz, 2 H), 4.70 (d, J=2.1 Hz, 1 H), 4.63 (s, 2 H), 4.39 (d, J=2.1Hz, 1 H), 4.12 (s, 2H).

A mixture of G2 (870 mg, 2.82 mmol) and 10% Pd/C (100 mg) in EtOH (10mL) and THF (5 mL) was degassed and filled with H₂ three times. Afterhydrogenating under 1 atm overnight, the mixture was filtered throughCelite. The filtrate was concentrated and column chromatographed to give563 mg (91%) of G3 as a clear oil;

1H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.6 Hz, 2 H), 7.99 (d, J=8.6 Hz, 2H), 4.57 (m, 1 H), 3.76 (m, 2 H), 1.93 (t, J=6.3 Hz, 1 H), 1.30 (d,J=6.2 Hz, 3 H); MS (ES) m/z: 243 (M+Na+).

Following general procedure 1 in Example A gave G4 (11%, clear oil); 1HNMR (400 MHz, CDCl₃) δ 7.47 (d, J=8.9 Hz, 2 H), 7.24 (s, 1 H), 7.21 (dd,J=8.5, 2.1 Hz, 1H), 6.76 (d, J=8.9 Hz, 2 H), 6.63 (d, J=8.5 Hz, 1 H),4.64 (s, 2 H), 4.46 (dd, J=12.0, 6.1 Hz, 1 H), 4.27 (q, J=7.1 Hz, 2 H),3.16 (dd, J=13.8, 5.3 Hz, 1 H), 2.90 (dd, J=13.8, 6.9 Hz, 1 H), 2.26 (s,3 H), 1.43 (d, J=5.9 Hz, 3 H), 1.30 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 451(M+Na+).

Following general procedure 2 in Example A gave Compound 7 (62%, solid);

1H NMR (300 MHz, MeOH-d4) δ 7.50 (d, J=8.6 Hz, 2 H), 7.21 (m, 2 H), 6.83(d, J=8.7 Hz, 2 H), 6.75 (d, J=7.4 Hz, 1 H), 4.62 (s, 2 H), 4.54 (dd,J=11.8, 6.0 Hz, 1 H), 3.12 (dd, J=13.9, 5.6 Hz, 1 H), 2.96 (dd, J=14.0,6.2 Hz, 1 H), 2.21 (s, 3 H), 1.41 (d, J=6.2 Hz, 3 H); MS (ES) m/z: 423(M+Na+); FAB-HRMS (M⁺). Calcd 400.0956, found 400.0944.

Example H

{3-Chloro-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-phenyl}-aceticacid

A mixture of (3-chloro-4-mercaptophenyl)acetic acid methyl ester H1 (758mg, 3.48 mmol; Sahoo, S. P., Preparation of arylthiazolidinediones asagonists of peroxisome proliferator activated receptor, WO99/32465),methanesulfonic acid 2-(4-trifluoromethyl-phenoxymethyl) pentyl ester H2(880 mg, 2.70 mmol), and Cs₂CO₃ (2.64 g, 8.10 mmol) in CH₃CN (8 mL) wasstirred for 2 h, diluted with water, and extracted with Et₂O. Thecombined organic layers were dried, concentrated, and columnchromatographed (EtOAc/hexane:1/7) to give 205 mg (17%) of H3; 1H NMR(400 MHz, CDCl₃) δ 7.51 (d, J=8.7 Hz, 2 H), 7.29 (s, 1 H), 7.27 (s, 1H), 7.08 (dd, J=8.1, 1.7 Hz, 1 H), 6.93 (d, J=8.6 Hz, 2 H), 4.09 (dd,J=9.3, 4.7 Hz, 1 H), 4.00 (dd, J=9.3, 5.8 Hz, 1 H), 3.69 (s, 3 H), 3.53(s, 2 H), 3.14 (dd, J=13.0, 7.0 Hz, 1 H), 3.06 (dd, J=13.0, 5.7 Hz, 1H), 2.06 (m, 1 H), 1.69-1.61 (m, 2 H), 0.99 (t, J=7.4 Hz, 3 H).

Following general procedure 2 in Example A gave Compound 9 (90%); 1H NMR(300 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.26 (m, 2 H), 7.06 (d,J=8.0 Hz, 1 H), 6.92 (d, J=8.6 Hz, 2 H), 4.08 (dd, J=9.3, 4.6 Hz, 1 H),3.99 (dd, J=9.3, 5.8 Hz, 1 H), 3.54 (s, 2 H), 3.14 (dd, J=13.0, 7.0 Hz,1 H), 3.05 (dd, J=13.0, 5.7 Hz, 1H), 2.06 (m, 1 H), 1.64 (m, 2 H), 0.99(t, J=7.4 Hz, 3 H); MS (ES) m/z: 455 (M+Na+).

Example I

{4-[3-Cyano-2-(4-trifluoromethyl-phenoxymethyl)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

A mixture of (4-mercapto-2-methylphenoxy)acetic acid ethyl ester A1c(453 mg, 2.00 mmol) and barium manganate (513 mg, 2.00 mmol) in CH₂Cl₂(5 mL) was stirred at room temperature for 20 min, filtered throughsilica gel, and washed with EtOAc/hexane (1/3). The filtrate wasconcentrated to give 802 mg (89%) of 11; 1H NMR (400 MHz, CDCl₃) δ 7.27(s, 1 H), 7.23 (dd, J=8.4, 2.3 Hz, 1 H), 6.61 (d, J=8.5 Hz, 1 H), 4.62(s, 2 H), 4.26 (q, J=7.1 Hz, 2 H), 2.25 (s, 3 H), 1.29 (t, J=7.1 Hz, 3H); MS (ES) m/z: 473 (M+Na+).

To a mixture of 2-hydroxymethylpropane-1,3-diol (500 mg, 4.71 mmol) inDMF (1.5 mL) and THF (3 mL) were added trifluoromethylphenol (822 mg,5.07 mmol) and triphenylphosphine (1.02 g, 3.90 mmol). After the mixturewas cooled to 0° C., diisopropyl azodicarboxylate (789 mg, 3.91 mmol)was introduced. The mixture was allowed to warm up to room temperature,stirred overnight, concentrated, and column chromatographed to provide200 mg (17%) of I2; 1H NMR (300 MHz, CDCl₃) δ 7.50 (d, J=8.7 Hz, 2 H),6.93 (d, J=8.6 Hz, 2 H), 4.05 (d, J=6.1 Hz, 2 H), 3.90-3.80 (m, 4 H),3.42 (brs, 2 H), 2.20 (m, 1 H); MS (ES) m/z: 273 (M+Na+).

To a mixture of I1 (97 mg, 0.22 mmol) and 12 (81 mg, 0.32 mmol) inpyridine (0.2 mL) was added tributylphosphine (44 mg, 0.22 mmol). Themixture was stirred overnight, diluted with 1 N HCl, and extracted withEt₂O. The extracts were dried, concentrated, and column chromatographed(EtOAc/hexane:2/5) to provide 54 mg (55%) of 13; 1H NMR (400 MHz, CDCl₃)δ 7.52 (d, J=8.9 Hz, 2 H), 7.22 (d, J=2.2 Hz, 1 H), 7.18 (dd, J=8.4, 2.3Hz, 1 H), 6.92 (d, J=8.8 Hz, 2 H), 6.59 (d, J=8.4 Hz, 1 H), 4.59 (s, 2H), 4.26 (q, J=7.1 Hz, 2 H), 4.16-4.09 (m, 2 H), 3.86 (d, J=5.3 Hz, 2H), 3.04 (d, J=6.8 Hz, 2 H), 2.26-2.20 (m, 1 H), 2.23 (s, 3 H), 1.29 (t,J=7.1 Hz, 3 H); MS (ES) m/z: 481 (M+Na+).

To a mixture of 13 (114 mg, 0.249 mmol) and triphenylphosphine (98 mg,0.37 mmol) in THF (2 mL) at 0° C. was added diisopropyl azodicarboxylate(75 mg, 0.37 mmol) and acetone cyanohydrin (32 mg, 0.38 mmol). Themixture was stirred at room temperature overnight, concentrated, andcolumn chromatographed to provide 57 mg (49%) of 14; 1H NMR (400 MHz,CDCl₃) δ 7.54 (d, J=8.7 Hz, 2 H), 7.23 (s, 1 H), 7.20 (dd, J=8.4, 2.2Hz, 1 H), 6.91 (d, J=8.7 Hz, 2 H), 6.60 (d, J=8.4 Hz, 1 H), 4.60 (s, 2H), 4.26 (q, J=7.1 Hz, 2 H), 4.13 (dd, J=9.5, 4.6 Hz, 1 H), 4.08 (dd,J=9.5, 6.0 Hz, 1 H), 3.08 (dd, J=14.0, 6.9 Hz, 1 H), 3.00 (dd, J=13.9,7.0 Hz, 1 H), 2.73 (dd, J=6.3, 1.8 Hz, 2 H), 2.37 (m, 1 H), 2.25 (s, 3H), 1.30 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 490 (M+Na+). Anal. Calcd forC₂₃H₂₄F₃NO₄S: C, 59.09; H, 5.17; N, 3.00. Found: C, 59.11; H, 5.12; N,2.93.

Following general procedure 2 in Example A gave Compound 10 (73%); 1HNMR (300 MHz, CD₃OD) δ 7.55 (d, J=8.6 Hz, 2 H), 7.23 (m, 2 H), 7.00 (d,J=8.6 Hz, 2 H), 6.71 (d, J=8.2 Hz, 1 H), 4.55 (s, 2 H), 4.12 (d, J=5.2Hz, 2 H), 3.11 (dd, J=14.0, 7.0 Hz, 1 H), 3.01 (dd, J=14.0, 6.7 Hz, 1H), 2.78 (d, J=6.3 Hz, 2 H), 2.33 (m, 1 H), 2.18 (s, 3 H); MS (ES) m/z:462 (M+Na+).

Example J

{4-[4-Cyano-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-aceticacid

To a mixture of 2-(2,2-diethoxyethyl)-1,3-propanediol J1 (500 mg, 2.60mmol), trifluoromethylphenol (357 mg, 2.20 mmol), and triphenylphosphine(525 mg, 2.00 mmol) in THF (5 mL) at 0° C. was added diisopropylazodicarboxylate (384 mg, 1.90 mmol). The mixture was allowed to warm upto room temperature, stirred overnight, diluted with water, andextracted with Et₂O. The combined organic layers were dried,concentrated, and column chromatographed (EtOAc/hexane:1/4) to provide436 mg (53%) of J2; 1H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.7 Hz, 2 H),6.94 (dd, J=8.8, 2.2 Hz, 2 H), 5.18 (m, 1 H), 4.15-4.03 (m, 2 H),3.92-3.88 (m, 1 H), 3.85-3.78 (m, 1 H), 3.77-3.67 (m, 2 H), 3.49-3.43(m, 1 H), 2.95-2.86 (m, 1 H), 2.28-2.18 (m, 1 H), 2.15-2.07 (m, 1 H),1.88-1.79 (m, 1 H), 1.23 (t, J=7.0 Hz, 6 H); MS (ES) m/z: 359 (M+Na+).

Following general procedure 1 in Example A provided J3 (56%); 1H NMR(400 MHz, CDCl₃) δ 7.50 (d, J=8.8 Hz, 2 H), 7.19 (d, J=2.1 Hz, 1 H),7.15 (dd, J=8.4, 2.3 Hz, 1 H), 6.88 (d, J=8.7 Hz, 2 H), 6.54 (d, J=8.4Hz, 1 H), 4.59 (t, J=5.7 Hz, 1H), 4.56 (s, 2 H), 4.25 (q, J=7.1 Hz, 2H), 4.11 (dd, J=9.3, 4.6 Hz, 1 H), 4.00 (dd, J=9.3, 5.6 Hz, 1 H),3.65-3.58 (m, 2 H), 3.48-3.43 (m, 2 H), 3.06-3.04 (m, 2 H), 2.26-2.20(m, 1 H), 2.20 (s, 3 H), 1.88 (m, 2 H), 1.29 (t, J=7.1 Hz, 3 H), 1.16(t, J=7.0 Hz, 3 H), 1.15 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 567 (M+Na+).Anal. Calcd for C₂₇H₃₅F₃O₆S: C, 59.54; H, 6.48. Found: C, 59.75; H,6.45.

A mixture of J3 (130 mg, 0.239 mmol) in trifluoroacetic acid (1.5 mL),water (1.5 mL), and CHCl₃ (6 mL) was stirred at room temperature for 3h, diluted with water, and extracted with CHCl₃. The organic phases weredried, concentrated, and column chromatographed (CH₂Cl₂) to afford 105mg (93%) of J4; 1H NMR (300 MHz, CDCl₃) δ 9.78 (s, 1 H), 7.51 (d, J=8.6Hz, 2 H), 7.21 (d, J=1.7 Hz, 1 H), 7.16 (dd, J=8.4, 2.2 Hz, 1 H), 6.88(d, J=8.6 Hz, 2 H), 6.58 (d, J=8.4 Hz, 1 H), 4.58 (s, 2 H), 4.25 (q,J=7.1 Hz, 2 H), 4.04 (d, J=4.9 Hz, 2 H), 3.07 (dd, J=13.7, 6.6 Hz, 1 H),2.97 (dd, J=13.7, 6.1 Hz, 1 H), 2.77-2.64 (m, 3 H), 2.23 (s, 3 H), 1.29(t, J=7.1 Hz, 3 H); MS (ES) m/z: 493 (M+Na+).

To a solution of J4 (100 mg, 0.213 mmol) in EtOH (1.2 mL) at 0° C. wasadded NaBH₄ (48 mg, 1.3 mmol). After stirring for 15 min at the sametemperature, the mixture was diluted with Et₂O, acidified with 1N HCl,and extracted with Et₂O. The combined organic layers were dried,concentrated, and column chromatographed to afford 93 mg (93%) of J5; 1HNMR (300 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.20 (d, J=1.8 Hz, 1 H),7.15 (dd, J=8.4, 2.2 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2 H), 6.56 (d, J=8.4Hz, 1 H), 4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.05 (m, 2 H), 3.73(t, J=6.4 Hz, 2 H), 3.03 (m, 2 H), 2.29-2.21 (m, 1 H), 2.21 (s, 3 H),1.82 (q, J=6.5 Hz, 2 H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 495(M+Na+). Anal. Calcd for C₂₃H₂₇F₃O₅S: C, 58.46; H, 5.76. Found: C,58.39; H, 5.53.

Replacing 13 with J5 and following the same procedure as in thepreparation of 14 in Example I provided J6 (65%); 1H NMR (300 MHz,CDCl₃) δ 7.53 (d, J=8.6 Hz, 2 H), 7.21 (d, J=1.7 Hz, 1 H), 7.18 (dd,J=8.4, 2.2 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2 H), 6.58 (d, J=8.4 Hz, 1 H),4.58 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.05-4.02 (m, 2 H), 3.00 (d,J=6.4 Hz, 2 H), 2.44 (t, J=7.4 Hz, 2 H), 2.26-2.16 (m, 1 H), 2.22 (s, 3H), 2.00-1.92 (m, 2 H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 504(M+Na+). Anal. Calcd for C₂₄H₂₆F₃NO₄S: C, 59.86; H, 5.44; N, 2.91.Found: C, 59.85; H, 5.31; N, 2.93.

Following general procedure 2 in Example A gave Compound 11 (94%); 1HNMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.6 Hz, 2 H), 7.19 (s, 1 H), 7.15 (d,J=8.2 Hz, 1H), 6.88 (d, J=8.6 Hz, 2 H), 6.58 (d, J=7.8 Hz, 1 H), 4.53(s, 2 H), 4.02 (m, 2 H), 2.98 (d, J=6.2 Hz, 2 H), 2.42 (t, J=7.3 Hz, 2H), 2.18 (m, 4 H), 1.97-1.90 (m, 2 H); MS (ES) m/z: 476 (M+Na+). Anal.Calcd for C₂₂H₂₂F₃NO₄S+0.3 H₂O: C 57.58; H, 4.96; N, 3.05. Found: C,57.40; H, 4.73; N, 2.96.

Example K

{4-[5-Cyano-2-(4-trifluoromethyl-phenoxymethyl)-pent-4-enylsulfanyl]-2-methyl-phenoxy}-aceticacid

A mixture of J4 (47 mg, 0.10 mmol) and (triphenylphosphoranylidene)acetonitrile (181 mg, 0.601 mmol) in CH₂Cl₂ (1 mL) was refluxedovernight, concentrated, and purified by column chromatography(EtOAc/hexane:1/9) to give a mixture of K1 and K2. K1: 1H NMR (300 MHz,CDCl₃) δ 7.54 (d, J=8.6 Hz, 2 H), 7.20 (d, J=1.7 Hz, 1 H), 7.16 (dd,J=8.4, 2.2 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2 H), 6.72-6.61 (m, 1 H), 6.58(d, J=8.4 Hz, 1 H), 5.33 (d, J=16.3 Hz, 1 H), 4.59 (s, 2 H), 4.26 (q,J=7.1 Hz, 2 H), 3.99 (d, J=5.1 Hz, 2 H), 2.95 (m, 2 H), 2.51 (m, 2 H),2.24 (s, 3 H), 2.24-2.17 (m, 1 H), 1.30 (t, J=7.1 Hz, 3 H); MS (ES) m/z:516 (M+Na+); K2: 1H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.6 Hz, 2 H), 7.21(s, 1 H), 7.17 (dd, J=8.4, 2.2 Hz, 1 H), 6.90 (d, J=8.6 Hz, 2 H), 6.58(d, J=8.4 Hz, 1 H), 6.49 (dt, J=10.9, 7.8 Hz, 1 H), 5.40 (d, J=10.9 Hz,1 H), 4.58 (s, 2 H), 4.26 (q, J=7.1 Hz, 2 H), 4.03-4.00 (m, 2 H), 2.98(m, 2 H), 2.73 (m, 2 H), 2.22 (m, 4 H), 1.30 (t, J=7.1 Hz, 3 H); MS (ES)m/z: 516 (M+Na+).

Using K1 as the starting material and following general procedure 2 inExample A gave Compound 12 (60%); 1H NMR (300 MHz, CDCl₃) δ 7.52 (d,J=8.6 Hz, 2 H), 7.17 (s, 1 H), 7.13 (dd, J=8.0 Hz, 1 H), 6.88 (d, J=8.6Hz, 2 H), 6.67-6.57 (m, 2 H), 5.28 (d, J=16.3 Hz, 1 H), 4.54 (s, 2 H),3.98 (d, J=5.0 Hz, 2 H), 2.93 (m, 2 H), 2.49 (t, J=6.9 Hz, 2 H), 2.19(s, 3 H), 2.19-2.13 (m, 1 H); MS (ES) m/z: 488 (M+Na+).

Example L

{4-[2-Methoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

A mixture of 4-trifluoromethylphenol (7.80 g, 48.1 mmol),2-chloromethyloxirane (11.2 g, 121 mmol), and Cs₂CO₃ (15.7 g, 48.2 mmol)in dioxane (8 mL) was refluxed for 3-4 h and then allowed to cool toroom temperature. Water and Et₂O were added, the organic phase wasseparated, and the aqueous phase was extracted with Et₂O. The combinedorganic layers were dried, concentrated, and column chromatographed(CH₂Cl₂/hexane: 1/1) to provide 8.40 g (80%) of L1; 1H NMR (300 MHz,CDCl₃) δ 7.55 (d, J=8.5 Hz, 2 H), 6.99 (d, J=8.5 Hz, 2 H), 4.29 (dd,J=11.1, 3.0 Hz, 1 H), 3.98 (dd, J=11.1, 5.8 Hz, 1 H), 3.37 (m, 1 H),2.93 (m, 1 H), 2.77 (dd, J=4.9, 2.6 Hz, 1 H).

To a mixture of L1 (2.57 g, 11.8 mmol) and(4-mercapto-2-methyl-phenoxy)acetic acid ethyl ester A1c (4.00 g, 17.7mmol) in THF (20 mL) was added 1.0 M tetrabutylammonium fluoride in THF(0.44 mL, 0.44 mmol). The reaction mixture was stirred at roomtemperature for 1.5 h, heated at 60° C. for 1 h, concentrated, andpurified by column chromatography to give 4.45 g (85%) of L2; 1H NMR(400 MHz, CDCl₃) δ 7.50 (d, J=8.9 Hz, 2 H), 7.25 (d, J=2.2 Hz, 1 H),7.21 (dd, J=8.4, 2.3 Hz, 1 H), 6.89 (d, J=8.8 Hz, 2 H), 6.58 (d, J=8.4Hz, 1 H), 4.58 (s, 2 H), 4.24 (q, J=7.1 Hz, 2 H), 4.05-4.00 (m, 3 H),3.13 (dd, J=13.7, 5.1 Hz, 1 H), 3.04 (dd, J=13.9, 6.5 Hz, 1 H), 2.92 (d,J=4.2 Hz, 1 H), 2.23 (s, 3 H), 1.28 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 467(M+Na+).

General Procedure 4 for Alkylation of Alcohols:

To a suspension of NaH (20 mg, 0.50 mmol, 60% in mineral oil) in THF (1mL) was added a solution of L2 (222 mg, 0.500 mmol) in THF (1 mL) atroom temperature. After 30 min, CH₃I (213 mg, 1.50 mmol) was introduced.The reaction mixture was stirred overnight, diluted with water, andextracted with Et₂O. The extracts were dried, concentrated, and purifiedby column chromatography (EtOAc/hexane:1/6) to give L3; 1H NMR (300 MHz,CDCl₃) δ 7.52 (d, J=8.6 Hz, 2 H), 7.24 (d, J=1.7 Hz, 1 H), 7.19 (dd,J=8.4, 2.1 Hz, 1 H), 6.91 (d, J=8.5 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H),4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.16 (dd, J=10.0, 4.0 Hz, 1 H),4.09 (dd, J=10.0, 5.0 Hz, 1 H), 3.67 (m, 1 H), 3.44 (s, 3 H), 3.13 (d,J=6.2 Hz, 2 H), 2.22 (s, 3 H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 481(M+Na+).

Following general procedure 2 in Example A gave Compound 14 (92%); 1HNMR (400 MHz, CDCl₃) δ 10.21 (brs, 1 H), 7.50 (d, J=8.6 Hz, 2 H), 7.23(s, 1 H), 7.20 (d, J=8.4 Hz, 1 H), 6.89 (d, J=8.5 Hz, 2 H), 6.58 (d,J=8.4 Hz, 1 H), 4.61 (s, 2 H), 4.16 (dd, J=10.0, 3.9 Hz, 1 H), 4.09 (dd,J=9.9, 4.9 Hz, 1 H), 3.68 (m, 1 H), 3.45 (s, 3 H), 3.14 (d, J=6.1 Hz, 2H), 2.20 (s, 3 H); MS (ES) m/z: 453 (M+Na+).

Example M

(R)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

(S)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

To a mixture of (R)-(+)-glycidol (2.00 g, 27.0 mmol),4-trifluoromethylphenol (4.38 g, 27.0 mmol), triphenylphosphine (7.08 g,27.0 mmol) in THF (50 mL) at 0° C. was slowly added diisopropylazodicarboxylate (5.46 g, 27.0 mmol). The reaction mixture was allowedto warm up to room temperature, stirred at the same temperatureovernight, diluted with water, and extracted with Et₂O. The extractswere dried and concentrated. The precipitated solid was filtered andrinsed with Et₂O. The filtrate was concentrated and columnchromatographed (CH₂Cl₂/hexane:1/2) to provide 4.50 g (76%) of M1;[α]_(D)+7.3° (c 1.0, CHCl₃); 1H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.7Hz, 2 H), 6.98 (d, J=8.7 Hz, 2 H), 4.29 (dd, J=11.1, 2.9 Hz, 1 H), 3.96(dd, J=11.1, 5.8 Hz, 1 H), 3.39-3.33 (m, 1 H), 2.92 (t, J=4.5 Hz, 1 H),2.76 (dd, J=4.9, 2.6 Hz, 1 H).

To a mixture of M1 (2.11 g, 9.68 mmol),(4-mercapto-2-methyl-phenoxy)acetic acid ethyl ester A1c (3.28 g, 14.5mmol) in THF (10 mL) was added 1.0 M tetrabutylammonium fluoride in THF(0.965 mL, 0.965 mmol). After stirring for 8 h, the solvent wasevaporated and the residue was purified by column chromatography twice(EtOAc/hexane:2/7 and EtOAc/CH₂Cl₂: 1/1) to give 3.69 g (85%) of M2;[α]_(D)+32.5° (c 1.0, CHCl₃); 1H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.8Hz, 2 H), 7.26 (s, 1 H), 7.23 (dd, J=8.4, 2.3 Hz, 1 H), 6.91 (d, J=8.8Hz, 2 H), 6.60 (d, J=8.4 Hz, 1 H), 4.59 (s, 2 H), 4.26 (q, J=7.1 Hz, 2H), 4.08-4.02 (m, 1 H), 4.05 (s, 2 H), 3.17-3.01 (m, 2 H), 2.70 (brs, 1H), 2.24 (s, 3 H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 467 (M+Na+).

Following general procedure 4 in Example L gave M3; [α]_(D)+38.9° (c1.0, CHCl₃); 1H NMR (300 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.24 (d,J=1.7 Hz, 1H), 7.19 (dd, J=8.4, 2.2 Hz, 1 H), 6.91 (d, J=8.6 Hz, 2 H),6.57 (d, J=8.4 Hz, 1 H), 4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.15(dd, J=9.9, 4.3 Hz, 1 H), 4.07 (dd, J=9.9, 5.1 Hz, 1 H), 3.76 (m, 1 H),3.61 (q, J=7.0 Hz, 2 H), 3.13-3.11 (m, 2 H), 2.23 (s, 3 H), 1.29 (t,J=7.1 Hz, 3 H), 1.18 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 495 (M+Na+). Anal.Calcd for C₂₃H₂₇F₃O₅S: C, 58.46; H, 5.76. Found: C, 58.83; H, 5.55.

Following general procedure 2 in Example A gave Compound 15;[α]_(D)+39.2° (c 1.0, CHCl₃); 1H NMR (300 MHz, CDCl₃) δ 7.51 (d, J=8.7Hz, 2 H), 7.23 (s, 1 H), 7.20 (dd, J=8.4, 2.1 Hz, 1 H), 6.91 (d, J=8.6Hz, 2 H), 6.59 (d, J=8.4 Hz, 1 H), 4.61 (s, 2 H), 4.14 (dd, J=9.9, 4.4Hz, 1 H), 4.08 (dd, J=9.9, 5.0 Hz, 1 H), 3.77 (m, 1 H), 3.61 (q, J=7.0Hz, 2 H), 3.20-3.07 (m, 2 H), 2.21 (s, 3 H), 1.19 (t, J=7.0 Hz, 3 H); MS(ES) m/z: 467 (M+Na+).

(R)-2-(4-Trifluoromethyl-phenoxymethyl)-oxirane

Following the same procedure as in the preparation of M1 gave M4 (74%);1H NMR (400 MHz, CDCl₃) δ 7.54 (d, J=9.0 Hz, 2 H), 6.98 (d, J=8.9 Hz, 2H), 4.29 (dd, J=11.1, 2.9 Hz, 1 H), 3.96 (dd, J=11.1, 5.8 Hz, 1 H), 3.37(m, 1 H), 2.92 (m, 1 H), 2.76 (dd, J=4.8, 2.6 Hz, 1 H); MS (ES) m/z: 241(M+Na+).

(S)-{4-[2-Hydroxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Following the same procedure as in the preparation of M2 prvided M5(88%);

1H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.7 Hz, 2 H), 7.26 (s, 1 H), 7.22(dd, J=8.4, 2.3 Hz, 1 H), 6.91 (d, J=8.7 Hz, 2 H), 6.59 (d, J=8.4 Hz, 1H), 4.59 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.07-4.01 (m, 3 H),3.17-3.01 (m, 2 H), 2.72 (brs, 1 H), 2.23 (s, 3 H), 1.29 (t, J=7.1 Hz, 3H); MS (ES) m/z: 467 (M+Na+).

(S)-{4-[2-Hydroxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Following general procedure 4 in Example L gave M6; 1H NMR (400 MHz,CDCl₃) δ 7.51 (d, J=8.7 Hz, 2 H), 7.24 (d, J=2.0 Hz, 1 H), 7.19 (dd,J=8.4, 2.3 Hz, 1 H), 6.91 (d, J=8.7 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H),4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.15 (dd, J=9.9, 4.3 Hz, 1 H),4.08 (dd, J=9.9, 5.1 Hz, 1 H), 3.76 (m, 1 H), 3.61 (q, J=7.0 Hz, 2 H),3.13-3.11 (m, 2 H), 2.22 (s, 3 H), 1.29 (t, J=7.1 Hz, 3 H), 1.18 (t,J=7.0 Hz, 3 H); MS (ES) m/z: 495 (M+Na+). Anal. Calcd for C₂₃H₂₇F₃O₅S:C, 58.46; H, 5.76. Found: C, 58.82; H, 5.37.

(S)-{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 16; 1H NMR (300MHz, CDCl₃) δ 7.50 (d, J=8.6 Hz, 2 H), 7.23 (s, 1 H), 7.19 (dd, J=8.4,1.9 Hz, 1H), 6.90 (d, J=8.6 Hz, 2 H), 6.58 (d, J=8.4 Hz, 1 H), 4.59 (s,2 H), 4.14 (dd, J=9.9, 4.4 Hz, 1 H), 4.08 (dd, J=9.9, 4.9 Hz, 1 H), 3.77(m, 1 H), 3.61 (q, J=7.0 Hz, 2 H), 3.13 (m, 2 H), 2.20 (s, 3 H), 1.18(t, J=7.0 Hz, 3 H); MS (ES) m/z: 467 (M+Na+).

{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Following general procedure 4 in Example L gave M7 (59%); 1H NMR (300MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.24 (d, J=1.7 Hz, 1 H), 7.19(dd, J=8.4, 2.2 Hz, 1 H), 6.91 (d, J=8.6 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1H), 4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.15 (dd, J=9.9, 4.3 Hz, 1H), 4.07 (dd, J=9.9, 5.1 Hz, 1 H), 3.76 (m, 1 H), 3.60 (q, J=7.0 Hz, 2H), 3.13-3.11 (m, 2 H), 2.22 (s, 3 H), 1.28 (t, J=7.1 Hz, 3 H), 1.18 (t,J=7.0 Hz, 3 H); MS (ES) m/z: 495 (M+Na+). Anal. Calcd for C₂₃H₂₇F₃O₅S:C, 58.46; H, 5.76. Found: C, 57.62; H, 5.52.

{4-[2-Ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 17 (94%); 1HNMR (400 MHz, CDCl₃) δ 7.50 (d, J=8.7 Hz, 2 H), 7.22 (s, 1 H), 7.18 (d,J=8.6 Hz, 1H), 6.90 (d, J=8.7 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H), 4.57(s, 2 H), 4.14 (dd, J=9.9, 4.3 Hz, 1 H), 4.07 (dd, J=9.8, 5.0 Hz, 1 H),3.77 (m, 1 H), 3.61 (q, J=7.0 Hz, 2 H), 3.18-3.08 (m, 2 H), 2.19 (s, 3H), 1.18 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 467 (M+Na+). Anal. Calcd forC₂₁H₂₃F₃O₅S+0.2 H₂O: C, 56.29; H, 5.26. Found: C, 56.23; H, 5.27.

{2-Methyl-4-[2-propoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-aceticacid ethyl ester

Replacing THF with DMF as solvent and following general procedure 4 inExample L gave M8 (12%); 1H NMR (300 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2H), 7.23 (d, J=1.7 Hz, 1 H), 7.19 (dd, J=8.4, 2.2 Hz, 1 H), 6.91 (d,J=8.6 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H), 4.57 (s, 2 H), 4.25 (q, J=7.1Hz, 2 H), 4.15 (dd, J=9.9, 4.3 Hz, 1H), 4.07 (dd, J=9.9, 5.1 Hz, 1 H),3.75 (m, 1 H), 3.50 (t, J=6.7 Hz, 2 H), 3.12 (d, J=6.2 Hz, 2 H), 2.23(s, 3 H), 1.63-1.51 (m, 2 H), 1.29 (t, J=7.1 Hz, 3 H), 0.90 (t, J=7.4Hz, 3 H); MS (ES) m/z: 509 (M+Na+).

{2-Methyl-4-[2-propoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 18 (92%); 1HNMR (400 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.24 (s, 1 H), 7.20 (d,J=8.3 Hz, 1H), 6.91 (d, J=8.5 Hz, 2 H), 6.59 (d, J=8.4 Hz, 1 H), 4.63(s, 2 H), 4.15 (dd, J=9.8, 4.3 Hz, 1 H), 4.08 (dd, J=9.8, 5.1 Hz, 1 H),3.76 (m, 1 H), 3.51 (t, J=6.6 Hz, 2 H), 3.15-3.13 (m, 2 H), 2.22 (s, 3H), 1.57 (m, 2 H), 0.90 (t, J=7.4 Hz, 3 H); MS (ES) m/z: 481 (M+Na+).

{4-[2-Butoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Replacing THF with DMF as solvent and following general procedure 4 inExample Lgave M9 (10%); 1H NMR (300 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2H), 7.23 (d, J=1.9 Hz, 1 H), 7.18 (dd, J=8.4, 2.2 Hz, 1 H), 6.91 (d,J=8.6 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H), 4.57 (s, 2 H), 4.26 (q, J=7.1Hz, 2 H), 4.15 (dd, J=9.9, 4.4 Hz, 1H), 4.07 (dd, J=9.9, 5.2 Hz, 1 H),3.75 (m, 1 H), 3.54 (t, J=6.6 Hz, 2 H), 3.12 (d, J=6.2 Hz, 2 H), 2.23(s, 3 H), 1.58-1.48 (m, 2 H), 1.41-1.34 (m, 2 H), 1.29 (t, J=7.1 Hz, 3H), 0.90 (t, J=7.3 Hz, 3 H); MS (ES) m/z: 523 (M+Na+).

{4-[2-Butoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 19 (92%); 1HNMR (400 MHz, CDCl₃) δ 7.47 (m, 2 H), 7.25-7.23 (m, 1 H), 7.13-7.12 (m,1 H), 6.87 (m, 2 H), 6.52 (m, 1 H), 4.37 (s, 2 H), 4.08-4.05 (m, 2 H),3.71 (m, 1 H), 3.52-3.50 (m, 2 H), 3.08 (m, 2 H), 2.11 (s, 3 H), 1.49(m, 2 H), 1.32-1.25 (m, 2 H), 0.87 (m, 3 H); MS (ES) m/z: 495 (M+Na+).Anal. Calcd for C₂₃H₂₇F₃O₅S+0.3 H₂O: C, 57.80; H, 5.82.

Found: C, 57.78; H, 6.00.

(R)-{4-[2-Allyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Following general procedure 4 in Example L gave M10; 1H NMR (400 MHz,CDCl₃) δ 7.52 (d, J=8.7 Hz, 2 H), 7.23 (s, 1 H), 7.19 (dd, J=8.4, 2.3Hz, 1 H), 6.91 (d, J=8.7 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H), 5.93-5.83(m, 1 H), 5.23 (dd, J=17.2, 1.5 Hz, 1 H), 5.16 (dd, J=10.3, 1.0 Hz, 1H), 4.58 (s, 2 H), 4.26 (q, J=7.1 Hz, 2 H), 4.17 (dd, J=9.9, 4.1 Hz, 1H), 4.13-4.05 (m, 3 H), 3.82 (m, 1 H), 3.13 (d, J=6.2 Hz, 2 H), 2.23 (s,3 H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 507 (M+Na+).

(R)-{4-[2-Allyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 20; 1H NMR (300MHz, MeOH-d4) δ 7.54 (d, J=8.6 Hz, 2 H), 7.24 (s, 1 H), 7.21 (d, J=2.1Hz, 1H), 6.99 (d, J=8.6 Hz, 2 H), 6.70 (d, J=8.1 Hz, 1 H), 5.93-5.80 (m,1 H), 5.20 (dd, J=17.2, 1.6 Hz, 1 H), 5.10 (dd, J=10.4, 1.3 Hz, 1 H),4.62 (s, 2 H), 4.19 (dd, J=10.3, 4.0 Hz, 1 H), 4.11 (dd, J=10.3, 5.1 Hz,1 H), 4.09-4.06 (m, 2 H), 3.81 (m, 1 H), 3.12 (d, J=6.4 Hz, 2 H), 2.18(s, 3 H); MS (ES) m/z: 479(M+Na+).

{4-[2-Allyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Replacing NaH with NaHMDS as a base and following general procedure 4 inExample L gave M11 (58%); 1H NMR (400 MHz, CDCl₃) δ 7.51 (d, J=8.8 Hz, 2H), 7.23 (d, J=2.1 Hz, 1 H), 7.19 (dd, J=8.4, 2.3 Hz, 1 H), 6.91 (d,J=8.8 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H), 5.93-5.83 (m, 1 H), 5.23 (dd,J=17.2, 1.5 Hz, 1 H), 5.16 (d, J=10.3 Hz, 1 H), 4.57 (s, 2 H), 4.25 (q,J=7.1 Hz, 2 H), 4.16 (dd, J=10.0, 4.1 Hz, 1 H), 4.11-4.08 (m, 3 H), 3.82(m, 1 H), 3.13 (d, J=6.1 Hz, 2 H), 2.22 (s, 3 H), 1.29 (t, J=7.1 Hz, 3H). Anal. Calcd for C₂₄H₂₇F₃O₅S: C, 59.49; H, 5.62. Found: C, 59.76; H,5.71.

{4-[2-Allyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 21 (90%); 1HNMR (400 MHz, CDCl₃) δ 7.49 (d, J=8.5 Hz, 2 H), 7.18 (s, 1 H), 7.14 (d,J=7.1 Hz, 1H), 6.89 (d, J=8.5 Hz, 2 H), 6.53 (m, 1 H), 5.91-5.82 (m, 1H), 5.21 (d, J=17.2, 1 H), 5.15 (d, J=10.3 Hz, 1 H), 4.44 (s, 2 H), 4.13(dd, J=9.8, 4.2 Hz, 1 H), 4.09-4.06 (m, 3H), 3.82 (m, 1 H), 3.11 (d,J=4.5 Hz, 2 H), 2.15 (s, 3 H); MS (ES) m/z: 455 (M−H+).

(R)-{4-[2-Methoxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Replacing NaH with iPr₂NEt as a base and following general procedure 4in Example L gave M12 (79%); [α]_(D)+47.8° (c 1.0, CHCl₃); 1H NMR (400MHz, CDCl₃) δ 7.51 (d, J=8.9 Hz, 2 H), 7.23 (d, J=2.2 Hz, 1 H), 7.18(dd, J=8.4, 2.3 Hz, 1 H), 6.90 (d, J=8.8 Hz, 2 H), 6.56 (d, J=8.4 Hz, 1H), 4.73 (s, 2 H), 4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.19-4.10 (m,2 H), 4.05 (m, 1 H), 3.39 (s, 3 H), 3.18-3.16 (m, 2 H), 2.22 (s, 3 H),1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 511 (M+Na+).

(R)-{4-[2-Methoxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 22 (95%);[α]_(D)+49.2° (c 1.0, CHCl₃); 1H NMR (400 MHz, CDCl₃) δ 7.51 (d, J=8.6Hz, 2 H), 7.23 (s, 1 H), 7.19 (d, J=8.4 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2H), 6.59 (d, J=8.4 Hz, 1 H), 4.74 (s, 2 H), 4.60 (s, 2 H), 4.19-4.10 (m,2 H), 4.05 (m, 1 H), 3.40 (s, 3 H), 3.19-3.17 (m, 2H), 2.21 (s, 3 H); MS(ES) m/z: 483 (M+Na+). Anal. Calcd for C₂₁H₂₃F₃O₆S: C, 54.78; H, 5.03.Found: C, 54.51; H, 4.90.

(S)-{4-[2-Methoxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Replacing NaH with iPr₂NEt as a base and following general procedure 4gave M13 (73%); 1H NMR (300 MHz, CDCl₃) δ 7.51 (d, J=8.7 Hz, 2 H), 7.22(s, 1 H), 7.18 (dd, J=8.4, 2.1 Hz, 1 H), 6.90 (d, J=8.6 Hz, 2 H), 6.57(d, J=8.4 Hz, 1 H), 4.73 (s, 2 H), 4.56 (s, 2 H), 4.25 (q, J=7.1 Hz, 2H), 4.18-4.13 (m, 1 H), 4.09-4.03 (m, 1 H), 3.39 (s, 3 H), 3.17 (d,J=6.2 Hz, 2 H), 2.22 (s, 3 H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 511(M+Na+).

(S)-{4-[2-Methoxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 23 (91%); 1HNMR (400 MHz, CDCl₃) δ 7.51 (d, J=8.7 Hz, 2 H), 7.23 (s, 1 H), 7.19 (d,J=8.4 Hz, 1H), 6.90 (d, J=8.6 Hz, 2 H), 6.59 (d, J=8.4 Hz, 1 H), 4.74(s, 2 H), 4.60 (s, 2 H), 4.19-4.10 (m, 2 H), 4.08-4.04 (m, 1 H), 3.40(s, 3 H), 3.19-3.17 (m, 2 H), 2.21 (s, 3 H); MS (ES) m/z: 483 (M+Na+).

{4-[2-Methoxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Following general procedure 4 in Example L gave M14 (84%); 1H NMR (400MHz, CDCl₃) δ 7.51 (d, J=8.7 Hz, 2 H), 7.23 (d, J=2.1 Hz, 1 H), 7.18(dd, J=8.4, 2.2 Hz, 1 H), 6.90 (d, J=8.7 Hz, 2 H), 6.56 (d, J=8.4 Hz, 1H), 4.73 (s, 2 H), 4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.19-4.10 (m,2 H), 4.05 (m, 1 H), 3.39 (s, 3 H), 3.18-3.16 (m, 2 H), 2.22 (s, 3 H),1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 511 (M+Na+). Anal. Calcd forC₂₃H₂₇F₃O₆S: C, 56.55; H, 5.57. Found: C, 56.68; H, 5.38.

{4-[2-Methoxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 24 (91%); 1HNMR (400 MHz, CDCl₃) δ 7.50 (d, J=8.6 Hz, 2 H), 7.23 (s, 1 H), 7.19 (d,J=8.4 Hz, 1H), 6.89 (d, J=8.5 Hz, 2 H), 6.58 (d, J=8.4 Hz, 1 H), 4.74(s, 2 H), 4.61 (s, 2 H), 4.18-4.10 (m, 2 H), 4.06 (m, 1 H), 3.40 (s, 3H), 3.19-3.17 (m, 2 H), 2.21 (s, 3 H); MS (ES) m/z: 483 (M+Na+). Anal.Calcd for C₂₁H₂₃F₃O₆S+0.2 H₂O: C, 54.35; H, 5.08.

Found: C, 54.25; H, 5.13.

{2-Methyl-4-[2-methylsulfanylmethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-aceticacid ethyl ester

A reaction mixture of L1b (1.08 g, 2.43 mmol), Ac₂O (2.56 mL, 27.2mmol), and DMSO (3.84 mL) was stirred at room temperature for 24 h, anddiluted with saturated NaHCO₃ and Et₂O. The organic phase was separated,washed with water (×3), dried, and column chromatographed(EtOAc/hexane:1/4) to give 61 mg (5%) of M15 as a by-product; 1H NMR(400 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.24 (s, 1 H), 7.20 (dd,J=8.4, 1.9 Hz, 1 H), 6.90 (d, J=8.6 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H),4.74 (d, J=6.0 Hz, 2 H), 4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H),4.21-4.10 (m, 3 H), 3.15 (d, J=6.0 Hz, 2 H), 2.23 (s, 3 H), 2.16 (s, 3H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 527

{2-Methyl-4-[2-methylsulfanylmethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 25 (92%); 1HNMR (300 MHz, CDCl₃) δ 9.45 (brs, 1 H), 7.51 (d, J=8.5 Hz, 2 H), 7.25(s, 1 H), 7.21 (d, J=8.5 Hz, 1 H), 6.90 (d, J=8.4 Hz, 2 H), 6.59 (d,J=8.4 Hz, 1 H), 4.74 (d, J=3.0 Hz, 2 H), 4.63 (s, 2 H), 4.19-4.10 (m, 3H), 3.16 (d, J=5.7 Hz, 2 H), 2.21 (s, 3 H), 2.16 (s, 3 H); MS (ES) m/z:499 (M+Na+).

{4-[2-Methoxycarbonylmethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Following general procedure 4 in Example L gave M16; 1H NMR (300 MHz,CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.24 (d, J=1.9 Hz, 1 H), 7.19 (dd,J=8.4, 2.2 Hz, 1 H), 6.91 (d, J=8.7 Hz, 2 H), 6.57 (d, J=8.4 Hz, 1 H),4.58 (s, 2 H), 4.28-4.23 (m, 5 H), 4.19-4.13 (m, 2 H), 3.89-3.86 (m, 1H), 3.69 (s, 2 H), 3.25-3.14 (m, 2 H), 2.23 (s, 3H), 1.29 (t, J=7.1 Hz,3 H); MS (ES) m/z: 539 (M+Na+).

{4-[2-Carboxymethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 26 (97%); 1HNMR (300 MHz, MeOH-d4) δ 7.53 (d, J=8.7 Hz, 2 H), 7.24 (s, 1 H), 7.22(dd, J=8.5, 2.2 Hz, 1 H), 6.97 (d, J=8.7 Hz, 2 H), 6.68 (d, J=8.4 Hz, 1H), 4.61 (s, 2 H), 4.24-4.15 (m, 4 H), 3.88-3.84 (m, 1 H), 3.20-3.16 (m,2 H), 2.17 (s, 3 H); MS (ES) m/z: 497 (M+Na+).

{4-[2-(5-Chloro-thiophen-2-ylmethoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Replacing NaH with sodium bis(trimethylsilyl)amide and following generalprocedure 4 gave M17 (26%); 1H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.6 Hz,2 H), 7.20 (d, J=1.7 Hz, 1 H), 7.15 (dd, J=8.4, 2.1 Hz, 1 H), 6.90 (d,J=8.6 Hz, 2 H), 6.72 (d, J=3.7 Hz, 1 H), 6.63 (d, J=3.7 Hz, 1 H), 6.57(d, J=8.4 Hz, 1 H), 4.67 (d, J=1.5 Hz, 2 H), 4.59 (s, 2 H), 4.26 (q,J=7.1 Hz, 2 H), 4.18 (dd, J=10.1, 3.9 Hz, 1 H), 4.09 (dd, J=10.1, 5.5Hz, 1 H), 3.92-3.85 (m, 1 H), 3.09 (d, J=6.2 Hz, 2 H), 2.23 (s, 3 H),1.30 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 597 (M+Na+).

{4-[2-(5-Chloro-thiophen-2-ylmethoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 27 (93%); 1HNMR (300 MHz, CDCl₃) δ 7.48 (d, J=8.6 Hz, 2 H), 7.11 (s, 1 H), 7.07 (d,J=8.3 Hz, 1H), 6.85 (d, J=8.6 Hz, 2 H), 6.68 (d, J=3.7 Hz, 1 H), 6.62(d, J=3.7 Hz, 1 H), 6.50 (d, J=7.9 Hz, 1 H), 4.64 (s, 2 H), 4.36 (s, 2H), 4.13-4.02 (m, 2 H), 3.89-3.84 (m, 1 H), 3.05 (d, J=4.8 Hz, 2 H),2.11 (s, 3 H); MS (ES) m/z: 545 (M−H+).

{4-[2-Benzyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Following general procedure 4 in Example L gave M18 (78%); 1H NMR (300MHz, CDCl₃) δ 7.50 (d, J=8.6 Hz, 2 H), 7.31-7.25 (m, 5 H), 7.19 (d,J=1.8 Hz, 1 H), 7.14 (dd, J=8.4, 2.2 Hz, 1 H), 6.89 (d, J=8.6 Hz, 2 H),6.55 (d, J=8.4 Hz, 1 H), 4.62 (d, J=4.9 Hz, 2 H), 4.57 (s, 2 H), 4.25(q, J=7.1 Hz, 2 H), 4.20-4.11 (m, 2 H), 3.87 (m, 1 H), 3.14 (d, J=6.1Hz, 2 H), 2.21 (s, 3 H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 557(M+Na+).

{4-[2-Benzyloxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 28 (93%); 1HNMR (300 MHz, CDCl₃) δ 7.50 (d, J=8.6 Hz, 2 H), 7.31-7.25 (m, 5 H), 7.19(d, J=1.8 Hz, 1 H), 7.14 (dd, J=8.4, 2.2 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2H), 6.56 (d, J=8.4 Hz, 1 H), 4.63 (m, 4 H), 4.20-4.08 (m, 2 H), 3.88 (m,1 H), 3.15 (d, J=6.7 Hz, 2 H), 2.19 (s, 3 H); MS (ES) m/z: 529 (M+Na+).

Example N

{4-[2-(4-Methoxy-phenoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[2-(4-Butyryl-phenoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

To a mixture of L1b (122 mg, 0.275 mmol) and 4-methoxyphenol (51 mg,0.41 mmol) in CH₂Cl₂ (3 mL) at 0° C. were slowly added1,1′-(azodicarbonyl)dipiperidine (104 mg, 0.412 mmol) followed by asolution of triphenylphosphine (108 mg, 0.412 mmol) in CH₂Cl₂ (3 mL).The reaction mixture was allowed to warm up to room temperature, stirredat the same temperature overnight, and filtered. The filtration wasconcentrated and column chromatographed (EtOAc/hexane:1/7) to provide110 mg (73%) of N1; MS (ES) m/z: 573 (M+Na+). Following generalprocedure 2 in Example A gave Compound 29 (91%); MS (ES) m/z: 545(M+Na+).

{4-[2-(4-Butyryl-phenoxy)-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

To a mixture of L1b (105 mg, 0.236 mmol) and1-(4-hydroxyphenyl)-butan-1-one (59 mg, 0.36 mmol) in CH₂Cl₂ (3 mL) at0° C. were slowly added 1,1′-(azodicarbonyl)dipiperidine (91 mg, 0.36mmol) followed by a solution of triphenylphosphine (94 mg, 0.36 mmol) inCH₂Cl₂ (3 mL). The reaction mixture was allowed to warm up to roomtemperature, stirred at the same temperature overnight, and filtered.The filtration was concentrated and column chromatographed(EtOAc/hexane:1/7) to provide 95 mg (68%) of N2; MS (ES) m/z: 613(M+Na+). Following general procedure 2 in Example A gave Compound 30(95%); MS (ES) m/z: 585 (M+Na+).

Example O

{3-Chloro-4-[2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-phenyl}-aceticacid

To a mixture of L1a (171 mg, 0.784 mmol) and(3-chloro-4-mercaptophenyl)acetic acid methyl ester H1 (170 mg, 0.787mmol; WO99/32465) in THF (3 mL) was added 1.0 M tetrabutylammoniumfluoride in THF (0.12 mL, 0.12 mmol). The reaction mixture was stirredat room temperature overnight, concentrated, and purified by columnchromatography (EtOAc/hexane:1/3) to give 261 mg (77%) of O1; 1H NMR(400 MHz, CDCl₃) δ 7.53 (d, J=8.8 Hz, 2 H), 7.38 (dd, J=8.1 Hz, 1 H),7.32 (d, J=1.7 Hz, 1 H), 7.12 (dd, J=8.1, 1.8 Hz, 1 H), 6.94 (d, J=8.8Hz, 2 H), 4.15-4.09 (m, 3 H), 3.70 (s, 3 H), 3.55 (s, 2 H), 3.27 (dd,J=13.8, 5.4 Hz, 1 H), 3.16 (dd, J=13.7, 6.5 Hz, 1 H), 2.75 (brs, 1 H);MS (ES) m/z: 457 (M+Na+). Anal. Calcd for C₁₉H₁₈ClF₃O₄S: C, 52.48; H,4.17. Found: C, 52.50; H, 4.27.

A solution of O1 (368 mg, 0.848 mmol) in THF (2.4 mL) was treated with1.0 M NaHMDS in THF (0.85 mL, 0.85 mmol) at −78° C. for 15 min. To themixture was added EtOTf (151 mg, 0.849 mmol) and the cooling bath wasremoved. The mixture was stirred at room temperature for 1 h, dilutedwith saturated NaHCO₃, and extracted with Et₂O. The extracts were dried,concentrated, and column chromatographed (EtOAc/hexane) to give 37 mg(9%) of O₂; 1H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.8 Hz, 2 H), 7.36 (dd,J=8.1 Hz, 1 H), 7.29 (d, J=1.8 Hz, 1 H), 7.10 (dd, J=8.1, 1.8 Hz, 1 H),6.95 (d, J=8.7 Hz, 2 H), 4.14 (dd, J=4.9, 1.4 Hz, 2 H), 3.85 (m, 1 H),3.70 (s, 3 H), 3.66 (q, J=7.0 Hz, 2 H), 3.54 (s, 2 H), 3.28 (dd, J=13.6,6.2 Hz, 1 H), 3.19 (dd, J=13.6, 5.8 Hz, 1 H), 1.20 (t, J=7.0 Hz, 3 H);MS (ES) m/z: 485 (M+Na+).

Following general procedure 2 in Example A gave Compound 32 (82%); 1HNMR (400 MHz, MeOH-d4) δ 7.56 (d, J=8.6 Hz, 2 H), 7.45 (d, J=8.1 Hz, 1H), 7.32 (d, J=1.3 Hz, 1 H), 7.16 (dd, J=8.1, 1.4 Hz, 1 H), 7.04 (d,J=8.6 Hz, 2 H), 4.22-4.14 (m, 2 H), 3.86 (m, 1 H), 3.65 (q, J=7.0 Hz, 2H), 3.55 (s, 2 H), 3.30-3.28 (m, 1 H), 3.22 (dd, J=13.8, 6.1 Hz, 1 H),1.15 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 471 (M+Na+).

Example P

{4-[2-Ethoxymethyl-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid

{2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-2-(4-trifluoromethyl-phenoxymethyl)-propylsulfanyl]-phenoxy}-aceticacid

To a solution of 13 (126 mg, 0.275 mmol) in THF (2 mL) at −78° C. wasadded 1.0 M sodium bis(trimethylsilyl)amide (0.27 mL, 0.27 mmol) in THF.After stirring for 5 min, ethyl trifluoromethanesulfonate (48 mg, 0.27mmol) was introduced and the cooling bath was removed. The mixture wasstirred for 30 min, quenched with saturated NaHCO₃, and extracted withEt₂O (×3). The extracts were dried, concentrated, and purified by columnchromatography (EtOAc/hexane:1/7) to provide 62 mg (47%) of P1; 1H NMR(300 MHz, CDCl₃) δ 7.51 (d, J=8.6 Hz, 2 H), 7.21 (d, J=2.2 Hz, 1 H),7.16 (dd, J=8.4, 2.2 Hz, 1 H), 6.91 (d, J=8.6 Hz, 2 H), 6.58 (d, J=8.4Hz, 1 H), 4.57 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.12 (dd, J=9.3, 5.4Hz, 1 H), 4.06 (dd, J=9.3, 5.4 Hz, 1 H), 3.58-3.55 (m, 2 H), 3.44 (q,J=7.0 Hz, 2 H), 3.04 (d, J=6.7 Hz, 2 H), 2.29 (m, 1 H), 2.23 (s, 3 H),1.29 (t, J=7.1 Hz, 3 H), 1.16 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 509(M+Na+).

Following general procedure 2 in Example A gave Compound 33 (88%); 1HNMR (300 MHz, CDCl₃) δ 7.50 (d, J=8.6 Hz, 2 H), 7.17 (s, 1 H), 7.14 (d,J=8.3, 1 H), 6.90 (d, J=8.6 Hz, 2 H), 6.57 (d, J=8.3 Hz, 1 H), 4.50 (s,2 H), 4.11 (dd, J=9.3, 5.4 Hz, 1 H), 4.04 (dd, J=9.3, 5.4 Hz, 1 H),3.57-3.54 (m, 2 H), 3.44 (q, J=7.0 Hz, 2 H), 3.02 (d, J=6.7 Hz, 2 H),2.27 (m, 1 H), 2.17 (s, 3 H), 1.15 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 481(M+Na+). Anal. Calcd for C₂₂H₂₅F₃O₅S: C, 57.63; H, 5.50. Found: C,57.77; H, 5.42.

{2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-2-(4-trifluoromethyl-phenoxymethyl)-propylsulfanyl]-phenoxy}-aceticacid ethyl ester

To a mixture of 13 (104 mg, 0.227 mmol), trifluoromethylphenol (56 mg,0.35 mmol), and triphenylphosphine (91 mg, 0.35 mmol) in THF (3 mL) at0° C. was added diisopropyl azodicarboxylate (70 mg, 0.35 mmol). Themixture was stirred at 0° C. for 30 min and room temperature for 7 h,concentrated, and column chromatographed (EtOAc/hexane:1/8) to provide110 mg (79%) of P2; 1H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.6 Hz, 4 H),7.22 (d, J=1.8 Hz, 1 H), 7.17 (dd, J=8.4, 2.3 Hz, 1 H), 6.92 (d, J=8.6Hz, 4 H), 6.56 (d, J=8.4 Hz, 1 H), 4.57 (s, 2 H), 4.26 (q, J=7.1 Hz, 2H), 4.21-4.16 (m, 4 H), 3.14 (d, J=6.7 Hz, 2 H), 2.54 (m, 1 H), 2.21 (s,3 H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 625 (M+Na+). Anal. Calcd forC₂₉H₂₈F₆O₅S: C, 57.80; H, 4.68. Found: C, 57.92; H, 4.52.

{2-Methyl-4-[3-(4-trifluoromethyl-phenoxy)-2-(4-trifluoromethyl-phenoxymethyl)-propylsulfanyl]-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 34 (84%); 1HNMR (300 MHz, MeOH-d4) δ 7.54 (d, J=8.1 Hz, 4 H), 7.22 (m, 2 H), 7.01(d, J=8.1

Hz, 4 H), 6.66 (d, J=8.1 Hz, 1 H), 4.56 (s, 2 H), 4.22 (m, 4 H), 3.16(d, J=6.2 Hz, 2H), 2.50 (m, 1 H), 2.14 (s, 3 H); MS (ES) m/z: 597(M+Na+). Anal. Calcd for C₂₇H₂₄F₆O₅S: C, 56.44; H, 4.21. Found: C,56.08; H, 4.01.

Example Q

{4-[4-Methoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-aceticacid

To a solution of J5 (117 mg, 0.248 mmol) in THF (2 mL) at −78° C. wasadded 1.0 M sodium bis(trimethylsilyl)amide (0.25 mL, 0.25 mmol) in THF.After stirring for 5 min, methyl trifluoromethanesulfonate (41 mg, 0.25mmol) was introduced and the cooling bath was removed. After thetemperature rising to room temperature, the mixture was quenched withwater and extracted with Et₂O (×3). The extracts were dried,concentrated, and purified by column chromatography (EtOAc/hexane:1/6)to provide 35 mg (29%) of Q1; 1H NMR (300 MHz, CDCl₃) δ 7.51 (d, J=8.6Hz, 2 H), 7.19 (d, J=1.6 Hz, 1 H), 7.14 (dd, J=8.4, 2.1 Hz, 1 H), 6.89(d, J=8.6 Hz, 2 H), 6.55 (d, J=8.4 Hz, 1 H), 4.56 (s, 2 H), 4.25 (q,J=7.1 Hz, 2 H), 4.08 (dd, J=9.3, 4.7 Hz, 1H), 3.99 (dd, J=9.3, 5.5 Hz, 1H), 3.45 (t, J=6.3 Hz, 2 H), 3.31 (s, 3 H), 3.04 (d, J=6.2 Hz, 2 H),2.26-2.18 (m, 1 H), 2.21 (s, 3 H), 1.82 (q, J=6.4 Hz, 2 H), 1.29 (t,J=7.1 Hz, 3 H); MS (ES) m/z: 509 (M+Na+).

Following general procedure 2 in Example A gave Compound 35 (95%); 1HNMR (300 MHz, CDCl₃) δ 7.49 (d, J=8.6 Hz, 2 H), 7.19-7.12 (m, 2 H), 6.87(d, J=8.6 Hz, 2 H), 6.55 (m, 1 H), 4.51 (s, 2 H), 4.07 (m, 1 H), 3.97(m, 1 H), 3.45 (t, J=6.0 Hz, 2 H), 3.30 (s, 3 H), 3.03 (d, J=6.2 Hz, 2H), 2.21-2.17 (m, 1 H), 2.17 (s, 3 H), 1.82 (q, J=6.3 Hz, 2 H); MS (ES)m/z: 481 (M+Na+).

{4-[4,4-Diethoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-aceticacid

Using J3 as the starting material and following general procedure 2 inExample A gave Compound 36 (85%); 1H NMR (300 MHz, CDCl₃) δ 7.49 (d,J=8.6 Hz, 2 H), 7.17 (s, 1 H), 7.14 (d, J=8.7 Hz, 1 H), 6.87 (d, J=8.6Hz, 2 H), 6.55 (d, J=7.9 Hz, 1H), 4.60 (t, J=5.6 Hz, 1 H), 4.54 (s, 2H), 4.10 (dd, J=9.3, 4.5 Hz, 1 H), 3.99 (dd, J=9.3, 5.7 Hz, 1 H),3.68-3.56 (m, 2 H), 3.51-3.40 (m, 2 H), 3.05-3.00 (m, 2 H), 2.25-2.17(m, 1 H), 2.17 (s, 3 H), 1.89-1.84 (m, 2 H), 1.16 (t, J=7.0 Hz, 3 H),1.15 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 539 (M+Na+).

{4-[4-Ethoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

Replacing methyl trifluoromethanesulfonate with ethyltrifluoromethanesulfonate and following the same procedure as in thepreparation of Q1 provided the title compound Q2 (23%); 1H NMR (300 MHz,CDCl₃) δ 7.50 (d, J=8.6 Hz, 2 H), 7.19 (d, J=1.7 Hz, 1 H), 7.14 (dd,J=8.4, 2.2 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2 H), 6.55 (d, J=8.4 Hz, 1 H),4.56 (s, 2 H), 4.25 (q, J=7.1 Hz, 2 H), 4.10 (dd, J=9.3, 4.6 Hz, 1 H),4.00 (dd, J=9.3, 5.6 Hz, 1 H), 3.51-3.40 (m, 4 H), 3.04 (d, J=6.1 Hz, 2H), 2.27-2.21 (m, 1 H), 2.21 (s, 3 H), 1.82 (q, J=6.5 Hz, 2 H), 1.29 (t,J=7.1 Hz, 3 H), 1.16 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 523 (M+Na+).

{4-[4-Ethoxy-2-(4-trifluoromethyl-phenoxymethyl)-butylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 37 (92%); 1HNMR (300 MHz, MeOH-d4) δ 7.53 (d, J=8.6 Hz, 2 H), 7.17 (m, 1 H), 7.14(d, J=2.1 Hz, 1 H), 6.98 (d, J=8.6 Hz, 2 H), 6.66 (d, J=8.2 Hz, 1 H),4.41 (s, 2 H), 4.12 (dd, J=9.5, 4.8 Hz, 1 H), 4.03 (dd, J=9.5, 5.5 Hz, 1H), 3.52-3.40 (m, 4 H), 3.00 (d, J=6.4 Hz, 2 H), 2.17 (s, 3 H),2.17-2.11 (m, 1 H), 1.83-1.76 (m, 2 H), 1.13 (t, J=7.0 Hz, 3 H); MS (ES)m/z: 495 (M+Na+).

Example R

{4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-2-methyl-phenoxy}-aceticacid

To a solution of R1 (1.00 g, 4.59 mmol) in Et₂O (20 mL) and MeOH (10 mL)was added 1.0 M (trimethylsilyl)diazomethane (9.16 mL, 9.16 mmol) inhexane. After stirring at room temperature for 1 h, the solvents wereremoved under reduced pressure. The residue was dissolved in Et₂O,washed with saturated NaHCO₃ and brine, dried, and concentrated to give1.04 g (98%) of R2; 1H NMR (300 MHz, CDCl₃) δ7.54 (d, J=8.1 Hz, 2 H),7.31 (d, J=8.1 Hz, 2 H), 3.67 (s, 3 H), 3.01 (t, J=7.7 Hz, 2 H), 2.65(t, J=7.7 Hz, 2 H); MS (ES) m/z: 255 (M+Na+).

To a solution of R2 (1.10 g, 4.74 mmol) in CH₂Cl₂ (20 mL) at −78° C. wasadded 1.0 M diisobutylaluminum hydride (4.74 mL, 4.74 mmol). The mixturewas stirred at −78° C. for 10 min and quenched with 10% HCl in MeOH (5mL). After warming to room temperature, the mixture was filtered and thefiltrate was concentrated and column chromatographed to provide 796 mg(83%) of R3; 1H NMR (400 MHz, CDCl₃) δ 9.82 (d, J=1.0 Hz, 1 H), 7.54 (d,J=8.1 Hz, 2 H), 7.31 (d, J=8.0 Hz, 2 H), 3.01 (t, J=7.4 Hz, 2 H), 2.82(t, J=7.3 Hz, 2 H).

A mixture of NaH (52 mg, 1.3 mmol; 60% in mineral oil) in DMSO (15 mL)was heated at 70° C. for 30 min and allowed to cool to room temperature.After diluting with THF (10 mL), to the mixture at 0° C. was slowlyadded a solution of trimethylsulfonium iodide (306 mg, 1.50 mmol) inDMSO (10 mL). After stirring for 10 min at 0° C., a solution of R3 (202mg, 1.00 mmol) in THF (10 mL) was introduced. Stirring was continued for1 h at 0° C. and the mixture was diluted with water and extracted withEt₂O. The extracts were dried, concentrated, and column chromatographed(EtOAc/hexane:1/7) to provide 147 mg (68%) of R4; 1H NMR (300 MHz,CDCl₃) δ 7.54 (d, J=8.1 Hz, 2 H), 7.31 (d, J=8.0 Hz, 2 H), 2.97-2.90 (m,1 H), 2.88-2.78 (m, 2 H), 2.75 (m, 1 H), 2.47 (dd, J=4.9, 2.7 Hz, 1 H),1.98-1.73 (m, 2 H).

A mixture of R4 (251 mg, 1.16 mmol), (4-mercapto-2-methylphenoxy)aceticacid ethyl ester A1c (394 mg, 1.74 mmol), and tetrabutylammoniumfluoride (0.12 mL, 0.12 mmol; 1.0 M in THF) in THF (5 mL) was stirred atroom temperature overnight and concentrated. The residue was purified bycolumn chromatography (EtOAc/hexane: 1/5) to give 250 mg (49%) of R5; 1HNMR (300 MHz, CDCl₃) δ 7.51 (d, J=8.0 Hz, 2 H), 7.26 (d, J=8.0 Hz, 2 H),7.23 (d, J=2.1 Hz, 1 H), 7.18 (dd, J=8.4, 2.3 Hz, 1 H), 6.61 (d, J=8.4Hz, 1 H), 4.62 (s, 2 H), 4.26 (q, J=7.1 Hz, 2 H), 3.63-3.55 (m, 1 H),3.01 (dd, J=13.6, 3.4 Hz, 1 H), 2.91-2.81 (m, 1 H), 2.79-2.66 (m, 2 H),2.56 (brs, 1 H), 2.25 (s, 3 H), 1.84-1.76 (m, 2 H), 1.30 (t, J=7.1 Hz, 3H); MS (ES) m/z: 465 (M+Na+).

A solution of R5 (44 mg, 0.10 mmol) in THF (0.5 mL) was treated with NaH(4.4 mg, 0.11 mmol; 60% in mineral oil) for 30 min and EtI (86 mg, 0.55mmol) was introduced. After stirring overnight, the mixture was dilutedwith water and extracted with Et₂O. The extracts were dried,concentrated, and purified by column chromatography (EtOAc/hexane) togive 18 mg (38%) of R6; 1H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2 H), 7.19 (d, J=1.8 Hz, 1 H), 7.11 (dd, J=8.4,2.2 Hz, 1 H), 6.59 (d, J=8.4 Hz, 1 H), 4.61 (s, 2 H), 4.26 (q, J=7.1 Hz,2 H), 3.58-3.50 (m, 1 H), 3.40-3.31 (m, 2 H), 3.06 (dd, J=13.3, 4.8 Hz,1 H), 2.85 (dd, J=13.3, 7.3 Hz, 1 H), 2.79-2.64 (m, 2 H), 2.25 (s, 3 H),2.06-1.96 (m, 1 H), 1.92-1.79 (m, 1 H), 1.29 (t, J=7.1 Hz, 3 H), 1.17(t, J=7.0 Hz, 3 H); MS (ES) m/z: 493 (M+Na+).

{4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-2-methyl-phenoxy}-aceticacid

Following general procedure 2 in Example A gave Compound 38 (93%); 1HNMR (300 MHz, CDCl₃) δ 9.25 (brs, 1 H), 7.51 (d, J=8.0 Hz, 2 H), 7.25(d, J=8.0 Hz, 2 H), 7.17 (d, J=1.5 Hz, 1 H), 7.09 (dd, J=8.4, 2.0 Hz, 1H), 6.58 (d, J=8.5 Hz, 1 H), 4.56 (s, 2 H), 3.61-3.51 (m, 1 H),3.42-3.31 (m, 2 H), 3.05 (dd, J=13.2, 4.9 Hz, 1 H), 2.84 (dd, J=13.2,7.1 Hz, 1 H), 2.80-2.63 (m, 2 H), 2.20 (s, 3 H), 2.05-1.94 (m, 1 H),1.92-1.81 (m, 1 H), 1.16 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 441 (M−H+).

{2-Methyl-4[2-methylsulfanylmethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-phenoxy}-aceticacid ethyl ester

A mixture of R5 (370 mg, 0.837 mmol) in Ac₂O (2.5 mL) and DMSO (4 mL)was stirred at room temperature for 24 h, diluted with water, andextracted with Et₂O. The extracts were dried, concentrated, and purifiedby column chromatography to give 51 mg (12%) of the title compound R7;1H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.1 Hz, 2 H), 7.27 (d, J=8.2 Hz, 2H), 7.22 (d, J=1.6 Hz, 1 H), 7.14 (dd, J=8.4, 2.1 Hz, 1 H), 6.61 (d,J=8.5 Hz, 1 H), 4.67-4.58 (m, 2 H), 4.61 (s, 2 H), 4.25 (q, J=7.1 Hz, 2H), 3.78 (m, 1 H), 3.10 (dd, J=13.4, 4.9 Hz, 1 H), 2.91 (dd, J=13.4, 6.9Hz, 1 H), 2.84-2.64 (m, 2 H), 2.26 (s, 3 H), 2.17 (s, 3 H), 2.09-1.86(m, 2 H), 1.29 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 525 (M+Na+).

{2-Methyl-4-[2-methylsulfanylmethoxy-4-(4-trifluoromethyl-phenyl)-butylsulfanyl]-phenoxy}-aceticAcid

Following general procedure 2 in Example A gave Compound 39 (90%); 1HNMR (300 MHz, CDCl₃) δ 7.48 (d, J=7.9 Hz, 2 H), 7.23 (d, J=7.8 Hz, 2 H),7.04 (m, 2 H), 6.46 (m, 1 H), 4.57 (s, 2 H), 4.53 (s, 2 H), 3.76 (m, 1H), 2.98 (m, 1 H), 2.88 (m, 1 H), 2.80-2.63 (m, 2 H), 2.11 (s, 3 H),2.06 (s, 3 H), 1.89 (m, 2 H); MS (ES) m/z: 473 (M−H+).

Example S

{4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-but-3-enylsulfanyl]-2-methyl-phenoxy}-aceticAcid

A mixture of (3-benzyloxypropyl)triphenyl-phosphonium bromide S1a (614mg, 1.25 mmol), 4-trifluoromethylbenzaldehyde (174 mg, 1.00 mmol), andK₂CO₃ (173 mg, 1.25 mmol) in isopropanol (1 mL) was refluxed for 5 h andconcentrated. The residue was partitioned between water and Et₂O. Theorganic phase was dried, concentrated, and column chromatographed (1%EtOAc in hexane) to give 260 mg (85%) of S1b as a mixture of trans andcis in the ratio of 3:1. Trans: 1H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.2Hz, 2 H), 7.42 (d, J=8.2 Hz, 2 H), 7.35-7.27 (m, 5 H), 6.49 (d, J=16.0Hz, 1 H), 6.35 (dt, J=15.9, 6.7 Hz, 1 H), 4.55 (s, 2 H), 3.61 (t, J=6.5Hz, 2 H), 2.55 (m, 2H).

A solution of S1b (50 mg, 0.16 mmol) in Ac₂O (0.8 mL) at 0° C. wastreated with trimethylsilyl trifluoromethanesulfonate (142 mg, 0.640mmol) for 15 min, and quenched with saturated NaHCO₃. The mixture wasextracted with Et₂O, and the extracts were dried, concentrated, andcolumn chromatographed to give acetates as a mixture of trans and cisproducts.

A solution of the trans and cis acetates (390 mg, 1.51 mmol) in THF (10mL) was treated with 1.0 M LiOH (3 mL, 3.0 mmol) at room temperatureovernight and extracted with Et₂O. The extracts were dried,concentrated, and column chromatographed to give S1c as a mixture oftrans and cis alcohols. Trans: 1H NMR (300 MHz, CDCl₃) δ 7.55 (d, J=8.2Hz, 2 H), 7.44 (d, J=8.2 Hz, 2 H), 6.53 (d, J=15.9 Hz, 1 H), 6.33 (dt,J=15.9, 7.1 Hz, 1 H), 3.79 (t, J=6.3 Hz, 2 H), 2.54-2.49 (m, 2 H); MS(ES) m/z: 239 (M+Na+).

Following general procedure 1 in Example A gave S1d (81%) as purecompound and a mixture of trans and cis. Trans: 1H NMR (300 MHz, CDCl₃)δ 7.53 (d, J=8.2 Hz, 2 H), 7.39 (d, J=8.2 Hz, 2 H), 7.24 (s, 1 H), 7.20(dd, J=8.4, 2.0 Hz, 1H), 6.63 (d, J=8.4 Hz, 1 H), 6.43 (d, J=16.0 Hz, 1H), 6.35-6.25 (m, 1 H), 4.61 (s, 2 H), 4.26 (q, J=7.1 Hz, 2 H), 2.96 (t,J=7.3 Hz, 2 H), 2.51 (q, J=7.0 Hz, 2 H), 2.26 (s, 3 H), 1.29 (t, J=7.1Hz, 3 H); MS (ES) m/z: 447 (M+Na+). Anal. Calcd for C₂₂H₂₃F₃O₃S: C,62.26; H, 5.46. Found: C, 62.43; H, 5.33.

Following general procedure 2 in Example A gave S1e Compound 40 (92%);

1H NMR (300 MHz, CDCl₃) δ 10.78 (brs, 1 H), 7.53 (d, J=8.2 Hz, 2 H),7.39 (d, J=8.1 Hz, 2 H), 7.25 (d, J=2.5 Hz, 1 H), 7.21 (dd, J=8.4, 2.0Hz, 1 H), 6.66 (d, J=8.4 Hz, 1 H), 6.43 (d, J=16.0 Hz, 1 H), 6.35-6.25(m, 1 H), 4.67 (s, 2 H), 2.97 (m, 2 H), 2.52 (q, J=6.9 Hz, 2 H), 2.25(s, 3 H); MS (ES) m/z: 419 (M+Na+).

A mixture of 4-trifluoromethylbenzaldehyde (174 mg, 1.00 mmol) and(triphenylphosphoranylidene)acetaldehyde (396 mg, 1.30 mmol) in CH₂Cl₂(6 mL) was stirred at room temperature for 20 h, concentrated, andcolumn chromatographed (EtOAc/hexane:1/8) to give 182 mg (70%) of S2a;1H NMR (400 MHz, CDCl₃) δ 9.76 (d, J=7.5 Hz, 1 H), 7.69 (m, 4 H), 7.51(d, J=16.0 Hz, 1 H), 6.78 (dd, J=16.0, 7.5 Hz, 1 H); MS (ES) m/z: 223(M+Na+).

To a solution of S2a (425 mg, 2.13 mmol) in THF (6 mL) at −78° C. wasadded CH₂I₂ (627 mg, 2.34 mmol) followed by 1.5 M MeLi (1.56 mL, 2.34mmol; complexed with LiBr in Et₂O). The mixture was allowed to graduallywarm up to room temperature, quenched with saturated NH₄Cl, andextracted with Et₂O. The extracts were dried, concentrated, and columnchromatographed (CH2Cl2/hexane: 2/3) to provide 341 mg (75%) of S2b; 1HNMR (400 MHz, CDCl₃) δ 7.58 (d, J=8.2 Hz, 2 H), 7.47 (d, J=8.2 Hz, 2 H),6.84 (d, J=16.0 Hz, 1 H), 5.99 (dd, J=16.0, 7.8 Hz, 1 H), 3.55-3.52 (m,1 H), 3.08 (dd, J=5.1, 4.3 Hz, 1 H), 2.79 (dd, J=5.2, 2.6 Hz, 1 H); MS(ES) m/z: 213 (M−H+).

Following general procedure 3 in Example E gave S2c; 1H NMR (400 MHz,CDCl₃) δ 7.55 (d, J=8.2 Hz, 2 H), 7.41 (d, J=8.1 Hz, 2 H), 7.29 (s, 1H), 7.26-7.24 (m, 1 H), 6.68-6.62 (m, 2 H), 6.24 (dd, J=16.0, 5.8 Hz, 1H), 4.62 (s, 2 H), 4.32 (m, 1 H), 4.27 (q, J=7.1 Hz, 2 H), 3.13 (dd,J=13.7, 3.9 Hz, 1 H), 2.92 (dd, J=13.7, 8.5 Hz, 1 H), 2.75 (brs, 1 H),2.26 (s, 3 H), 1.30 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 463 (M+Na+).

Following general procedure 2 in Example A gave S2d Compound 41 (91%);

1H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.2 Hz, 2 H), 7.40 (d, J=8.2 Hz, 2H), 7.28-7.25 (m, 2 H), 6.68-6.63 (m, 2 H), 6.24 (dd, J=16.0, 5.7 Hz, 1H), 4.67 (s, 2 H), 4.34 (m, 1 H), 3.14 (m, 1 H), 2.99-2.95 (m, 1 H),2.24 (s, 3 H); MS (ES) m/z: 411 (M−H+).

{4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-but-3-enylsulfanyl]-2-methyl-phenoxy}-aceticAcid Ethyl Ester

Following general procedure 4 in Example L gave S3 (35%); 1H NMR (300MHz, CDCl₃) δ 7.56 (d, J=8.2 Hz, 2 H), 7.42 (d, J=8.2 Hz, 2 H), 7.23 (s,1 H), 7.19 (dd, J=8.4, 2.1 Hz, 1 H), 6.61 (s, 1 H), 6.57 (d, J=8.9 Hz, 1H), 6.17 (dd, J=16.0, 7.3 Hz, 1 H), 4.60 (s, 2 H), 4.26 (q, J=7.1 Hz, 2H), 3.99 (q, J=6.7 Hz, 1 H), 3.60-3.52 (m, 1 H), 3.48-3.38 (m, 1 H),3.16 (dd, J=13.3, 6.3 Hz, 1 H), 2.99 (dd, J=13.3, 6.5 Hz, 1 H), 2.23 (s,3 H), 1.30 (t, J=7.1 Hz, 3 H), 1.21 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 491(M+Na+).

{4-[2-Ethoxy-4-(4-trifluoromethyl-phenyl)-but-3-enylsulfanyl]-2-methyl-phenoxy}-aceticAcid

Following general procedure 2 in Example A gave Compound 42 (93%); 1HNMR (300 MHz, CDCl₃) δ 7.56 (d, J=8.1 Hz, 2 H), 7.42 (d, J=8.1 Hz, 2 H),7.24 (s, 1 H), 7.21 (d, J=8.5 Hz, 1 H), 6.64-6.56 (m, 2 H), 6.21-6.09(dd, J=16.0, 7.3 Hz, 1H), 4.65 (s, 2 H), 4.00 (q, J=6.6 Hz, 1 H),3.61-3.53 (m, 1 H), 3.49-3.39 (m, 1 H), 3.16-2.97 (m, 2 H), 2.22 (s, 3H), 1.21 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 463 (M+Na+).

Example T

Following general procedure 2 in Example A and using M2 gave Compound 43(90%); [α]_(D)+54.5° (c 1.0, MeOH); ¹H NMR (300 MHz, CD₃OD) δ 7.54 (d,J=8.6 Hz, 2 H), 7.23 (m, 2 H), 6.99 (d, J=8.6 Hz, 2 H), 6.69 (d, J=8.2Hz, 1 H), 4.62 (s, 2 H), 3.96-4.12 (m, 3 H), 3.13 (dd, J=6.5, 13.8 Hz, 1H), 3.02 (dd, J=5.8, 13.8 Hz, 1 H), 2.18 (s, 3 H); MS (ES) m/z: 439(M+Na⁺). Anal. Calcd for C₁₉H₁₉F₃O₅S: C, 54.80; H, 4.60. Found: C,54.94; H, 4.51.

Example U

A mixture of (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester U1(196.2 mg, 1.0 mmol), which can be readily made according to, forexample, Sznaidman et al., Bioorganic & Medicinal Chemistry Letters 13(2003) 1517-1521, L1 (327.3 mg, 1.5 mmol), and Cs₂CO₃ (488.8 mg, 1.5mmol) in actonitrile (4 mL) was refluxed for 4 h. Water and ether wereadded, the organic layer was separated, and the aqueous layer wasextracted with ether. The combined organic extracts were combined,dried, concentrated, and column chromatographed (EtOAc/hexane:1/2) togive 327.4 mg (79%) of U2; ¹H NMR (300 MHz, CDCl₃) δ 7.55 (d, J=8.8 Hz,2 H), 6.99 (d, J=8.8 Hz, 2 H), 6.77 (s, 1 H), 6.67 (m, 2 H), 4.60 (s, 2H), 4.37 (m, 1 H), 4.18 (m, 2 H), 4.10 (m, 2 H), 3.79 (s, 3H), 2.56 (br.s, 1 H), 2.27 (s, 3 H); MS (ES) m/z: 437 (M+Na⁺).

Replacing O1 with U2 and following the procedure for preparation of O2in Example O gave U3 (51%); ¹H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.7 Hz,2 H), 6.99 (d, J=8.7 Hz, 2 H), 6.76 (s, 1 H), 6.66 (m, 2 H), 4.59 (s, 2H), 4.23 (m, 1 H), 4.15 (m, 1 H), 4.09 (m, 2 H), 4.01 (m, 1H), 3.79 (s,3H), 3.75 (q, J=6.9 Hz, 2 H), 2.26 (s, 3H), 1.25 (t, J=7.0 Hz, 3 H); MS(ES) m/z: 465 (M+Na⁺).

Following the general procedure 2 in Example A gave Compound 44 (92%);

¹H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=8.7 Hz, 2 H), 6.98 (d, J=8.7 Hz, 2H), 6.77 (s, 1 H), 6.68 (m, 2 H), 4.61 (s, 2 H), 4.23 (m, 1 H), 4.17 (m,1 H), 4.09 (m, 2 H), 4.01 (m, 1H), 3.79 (s, 3H), 3.76 (q, J=7.0 Hz, 2H), 2.26 (s, 3 H), 1.25 (t, J=7.0 Hz, 3 H); MS (ES) m/z: 427 (M−H⁺).

Following the general procedure 2 in Example A, hydrolysis of U2 gaveCompound 45 (93%); ¹H NMR (300 MHz, CD₃OD) δ 7.57 (d, J=8.7 Hz, 2 H),7.10 (d, J=8.6 Hz, 2 H), 6.79 (s, 1 H), 6.72 (m, 2 H), 4.59 (s, 2 H),4.26 (m, 1 H), 4.11-4.21 (m, 2 H), 4.06 (m, 2 H), 2.22 (s, 3 H); MS (ES)m/z: 423 (M+Na⁺).

D. Formulation and Administration

The present compounds are PPAR delta agonists and are therefore usefulin treating or inhibiting the progression of PPAR delta mediatedconditions, such as diabetes, cardiovascular diseases, Metabolic XSyndrome, hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, obesity, andcomplications thereof. For instance, complications of diabetes includesuch conditions as neuropathy, nephropathy, and retinopathy.

The invention features a method for treating a subject with a PPAR deltamediated disease, said method comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention. The invention also provides amethod for treating or inhibiting the progression of diabetes orimpaired glucose tolerance in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising a compound of the invention.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. To prepare thesepharmaceutical compositions, an effective amount of a particularcompound, in base or acid addition salt form, as the active ingredientis intimately mixed with a pharmaceutically acceptable carrier.

A carrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for oral administration or parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. These include water, glycols,oils, alcohols and the like in the case of oral liquid preparations suchas suspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. In view oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are generally employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Such additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of the compounds of formulaI, due to their increased water solubility over the corresponding baseform, are more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification herein refers to physically discrete units suitable asunitary dosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

Pharmaceutically acceptable acid addition salts include thetherapeutically active non-toxic acid addition salts of disclosedcompounds. The latter can conveniently be obtained by treating the baseform with an appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, palmoic andthe like acids. The term addition salt also comprises the solvates whichthe disclosed compounds, as well as the salts thereof, are able to form.Such solvates are for example hydrates, alcoholates and the like.Conversely the salt form can be converted by treatment with alkali intothe free base form.

Stereoisomeric forms define all the possible isomeric forms which thecompounds of Formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically isomeric forms, said mixtures containingall diastereomers and enantiomers of the basic molecular structure. Morein particular, stereogenic centers may have the (R)-or(S)-configuration; substituents on bivalent cyclic saturated radicalsmay have either the cis-or trans-configuration. The inventionencompasses stereochemically isomeric forms including diastereoisomers,as well as mixtures thereof in any proportion of the disclosedcompounds. The disclosed compounds may also exist in their tautomericforms. Such forms although not explicitly indicated in the above andfollowing formulae are intended to be included within the scope of thepresent invention.

Those of skill in the treatment of disorders or conditions mediated bythe PPAR delta could easily determine the effective daily amount fromthe test results presented hereinafter and other information. In generalit is contemplated that a therapeutically effective dose would be from0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01 mg/kg to0.5 mg/kg body weight. It may be appropriate to administer thetherapeutically effective dose as two, three, four or more sub-doses atappropriate intervals throughout the day. Said sub-doses may beformulated as unit dosage forms, for example, containing 0.05 mg to 250mg or 750 mg, and in particular 0.5 to 50 mg of active ingredient perunit dosage form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25mg, and 35 mg dosage forms. Compounds of the invention may also beprepared in time-release or subcutaneous or transdermal patchformulations. Disclosed compound may also be formulated as a spray orother topical or inhalable formulations.

The exact dosage and frequency of administration depends on theparticular compound of Formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the patient may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated patient and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned herein are therefore only guidelines.

The next section includes detailed information relating to the use ofthe disclosed compounds and compositions.

E. Use

The compounds of the present invention are pharmaceutically active, forexample, as PPAR delta agonists. According to one aspect of theinvention, the compounds are preferably selective PPAR delta agonists,having an activity index (e.g., PPAR delta potency over PPAR alpha/gammapotency) of 10 or more, and preferably 15, 25, 30, 50 or 100 or more.

According to the invention, the disclosed compounds and compositions areuseful for the amelioration of symptoms associated with, the treatmentof, and the prevention of, the following conditions and diseases: phaseI hyperlipidemia, pre-clinical hyperlipidemia, phase II hyperlipidemia,hypertension, CAD (coronary artery disease), coronary heart disease, andhypertriglyceridemia. Preferred compounds of the invention are useful inlowering serum levels of low-density lipoproteins (LDL), intermediatedensity lipoprotein (IDL), and/or small-density LDL and otheratherogenic molecules, or molecules that cause atheroscleroticcomplications, thereby reducing cardiovascular complications. Preferredcompounds also are useful in elevating serum levels of high-densitylipoproteins (HDL), in lowering serum levels of triglycerides, LDL,and/or free fatty acids. It is also desirable to lower fasting plasmaglucose (FPG)/HbA1c.

The invention also features pharmaceutical compositions which include,without limitation, one or more of the disclosed compounds, andpharmaceutically acceptable carrier or excipient.

1. Dosages

Those skilled in the art will be able to determine, according to knownmethods, the appropriate dosage for a patient, taking into accountfactors such as age, weight, general health, the type of symptomsrequiring treatment, and the presence of other medications. In general,an effective amount will be between 0.1 and 1000 mg/kg per day,preferably between 1 and 300 mg/kg body weight, and daily dosages willbe between 10 and 5000 mg for an adult subject of normal weight.Capsules, tablets or other formulations (such as liquids and film-coatedtablets) may be of between 5 and 200 mg, such as 10, 15, 25, 35, 50 mg,60 mg, and 100 mg and can be administered according to the disclosedmethods.

2. Formulations

Dosage unit forms include tablets, capsules, pills, powders, granules,aqueous and nonaqueous oral solutions and suspensions, and parenteralsolutions packaged in containers adapted for subdivision into individualdoses. Dosage unit forms can also be adapted for various methods ofadministration, including controlled release formulations, such assubcutaneous implants. Administration methods include oral, rectal,parenteral (intravenous, intramuscular, subcutaneous), intracisternal,intravaginal, intraperitoneal, intravesical, local (drops, powders,ointments, gels or cream), and by inhalation (a buccal or nasal spray).

Parenteral formulations include pharmaceutically acceptable aqueous ornonaqueous solutions, dispersion, suspensions, emulsions, and sterilepowders for the preparation thereof. Examples of carriers include water,ethanol, polyols (propylene glycol, polyethylene glycol), vegetableoils, and injectable organic esters such as ethyl oleate. Fluidity canbe maintained by the use of a coating such as lecithin, a surfactant, ormaintaining appropriate particle size. Carriers for solid dosage formsinclude (a) fillers or extenders, (b) binders, (c) humectants, (d)disintegrating agents, (e) solution retarders, (f) absorptionaccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and(j) propellants.

Compositions may also contain adjuvants such as preserving, wetting,emulsifying, and dispensing agents; antimicrobial agents such asparabens, chlorobutanol, phenol, and sorbic acid; isotonic agents suchas a sugar or sodium chloride; absorption-prolonging agents such asaluminum monostearate and gelatin; and absorption-enhancing agents.

3. Combination Therapy

The compounds of the present invention may be used in combination withother pharmaceutically active agents. These agents include lipidlowering agents, and blood pressure lowering agents such as statin drugsand the fibrates.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term‘jointly effective amount’ as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term ‘jointlyeffective amount’ refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that treats or inhibitsin a subject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician. Thus, thepresent invention provides combinations of two or more drugs wherein,for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both (ormore) drugs are administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

Anti-diabetic agents include thiazolidinedione and non-thiazolidinedioneinsulin sensitizers, which decrease peripheral insulin resistance byenhancing the effects of insulin at target organs and tissues.

Some of the following agents are known to bind and activate the nuclearreceptor peroxisome proliferator-activated receptor-gamma (PPARγ) whichincreases transcription of specific insulin-responsive genes. Examplesof PPAR-gamma agonists are thiazolidinediones such as:

-   -   (1) rosiglitazone        (2,4-thiazolidinedione,5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-,        (Z)-2-butenedioate (1:1) or        5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as AVANDIA; also known as BRL 49653, BRL 49653C, BRL        49653c, SB 210232, or rosiglitazone maleate);    -   (2) pioglitazone (2,4-thiazolidinedione,        5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-,        monohydrochloride, (+−)-or        5-((4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)methy)-2,4-thiazolidinedione,        known as ACTOS, ZACTOS, or GLUSTIN; also known as AD 4833, U        72107, U 72107A, U 72107E, pioglitazone hydrochloride (USAN));    -   (3) troglitazone        (5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as NOSCAL, REZULIN, ROMOZIN, or PRELAY; also known as        CI-991, CS 045, GR 92132, GR 92132×);    -   (4) isaglitazone        ((+)-5-[[6-[(2-fluorophenyl)methoxy]-2-naphthalenyl]methyl]-2,4-thiazolidinedione        or        5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl-2,4-thiazolidinedione        or        5-(6-(2-fluorobenzyloxy)naphthalen-2-ylmethyl)thiazolidine-2,4-dione,        also known as MCC-555 or neoglitazone); and    -   (5) 5-BTZD.

Additionally, the non-thiazolidinediones that act as insulin sensitizingagents include, but are not limited to:

-   -   (1) JT-501 (JTT 501, PNU-1827, PNU-716-MET-0096, or PNU 182716:        isoxazolidine-3,5-dione,        4-((4-(2-phenyl-5-methyl)-1,3-oxazolyl)ethylphenyl-4)methyl-);    -   (2) KRP-297        (5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-(trifluoromethyl)benzyl)benzamide        or        5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide);        and    -   (3) Farglitazar (L-tyrosine,        N-(2-benzoylphenyl)-o-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-or        N-(2-benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-L-tyrosine,        or GW2570 or GI-262570).

Other agents have also been shown to have PPAR modulator activity suchas PPAR gamma, SPPAR gamma, and/or PPAR delta/gamma agonist activity.Examples are listed below:

-   -   (1) AD 5075;    -   (2) R 119702        ((+−)-5-(4-(5-Methoxy-1H-benzimidazol-2-ylmethoxy)benzyl)thiazolin-2,4-dione        hydrochloride, or CI 1037 or CS 011);    -   (3) CLX-0940 (peroxisome proliferator-activated receptor alpha        agonist/peroxisome proliferator-activated receptor gamma        agonist);    -   (4) LR-90 (2,5,5-tris(4-chlorophenyl)-1,3-dioxane-2-carboxylic        acid, PPARdelta/γ agonist);    -   (5) Tularik (PPARγ agonist);    -   (6) CLX-0921 (PPARγ agonist);    -   (7) CGP-52608 (PPAR agonist);    -   (8) GW-409890 (PPAR agonist);    -   (9) GW-7845 (PPAR agonist);    -   (10) L-764406 (PPAR agonist);    -   (11) LG-101280 (PPAR agonist);    -   (12) LM-4156 (PPAR agonist);    -   (13) Risarestat (CT-112);    -   (14) YM 440 (PPAR agonist);    -   (15) AR-H049020 (PPAR agonist);    -   (16) GW 0072        (4-(4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazolidinyl)butyl)benzoic        acid);    -   (17) GW 409544 (GW-544 or GW-409544);    -   (18) NN 2344 (DRF 2593);    -   (19) NN 622 (DRF 2725);    -   (20) AR-H039242 (AZ-242);    -   (21) GW 9820 (fibrate);    -   (22) GW 1929        (N-(2-benzoylphenyl)-O-(2-(methyl-2-pyridinylamino)ethyl)-L-tyrosine,        known as GW 2331, PPAR alpha/γ agonist);    -   (23) SB 219994        ((S)-4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)benzen        epropanoic acid or        3-(4-1-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2        (S)-(2,2,2-trifluoroethoxy)propionic acid or benzenepropanoic        acid,4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)        (alphaS) PPARalpha/γ agonist);    -   (24) L-796449 (PPAR alpha/γ agonist);    -   (25) Fenofibrate (Propanoic acid,        2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-, 1-methylethyl ester,        known as TRICOR, LIPCOR, LIPANTIL, LIPIDIL MICRO PPAR alpha        agonist);    -   (26) GW-9578 (PPAR alpha agonist);    -   (27) GW-2433 (PPAR alpha/γ agonist);    -   (28) GW-0207 (PPARγ agonist);    -   (29) LG-100641 (PPARγ agonist);    -   (30) LY-300512 (PPARγ agonist);    -   (31) NID525-209 (NID-525);    -   (32) VDO-52 (VDO-52);    -   (33) LG 100754 (peroxisome proliferator-activated receptor        agonist);    -   (34) LY-510929 (peroxisome proliferator-activated receptor        agonist);    -   (35) bexarotene        (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoic        acid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as        LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO 264455); and    -   (36) GW-1536 (PPAR alpha/γ agonist).

(B) Other insulin sensitizing agents include, but are not limited to:

-   -   (1) INS-1 (D-chiro inositol or        D-1,2,3,4,5,6-hexahydroxycyclohexane);    -   (2) protein tyrosine phosphatase 1 B (PTP-1 B) inhibitors;    -   (3) glycogen synthase kinase-3 (GSK3) inhibitors;    -   (4) beta 3 adrenoceptor agonists such as ZD 2079        ((R)-N-(2-(4-(carboxymethyl)phenoxy)ethyl)-N-(2-hydroxy-2-phenethyl)ammonium        chloride, also known as ICI D 2079) or AZ 40140;    -   (5) glycogen phosphorylase inhibitors;    -   (6) fructose-1,6-bisphosphatase inhibitors;    -   (7) chromic picolinate, vanadyl sulfate (vanadium oxysulfate);    -   (8) KP 102 (organo-vanadium compound);    -   (9) chromic polynicotinate;    -   (10) potassium channel agonist NN 414;    -   (11) YM 268 (5,5′-methylene-bis(1,4-phenylene)bismethylenebis        (thiazolidine-2,4-dione);    -   (12) TS 971;    -   (13) T 174        ((+−)-5-(2,4-dioxothiazolidin-5-ylmethyl)-2-(2-naphthylmethyl)benzoxazole);    -   (14) SDZ PGU 693 ((+)-trans-2        (S-((4-chlorophenoxy)methyl)-7alpha-(3,4-dichlorophenyl)tetrahydropyrrolo        (2,1-b) oxazol-5(6H)-one);    -   (15) S15261        ((−)-4-(2-((9H-fluoren-9-ylacetyl)amino)ethyl)benzoic acid        2-((2-methoxy-2-(3-(trifluoromethyl)phenyl)ethyl)amino)ethyl        ester);    -   (16) AZM 134 (Alizyme);    -   (17) ARIAD;    -   (18) R 102380;    -   (19) PNU 140975 (1-(hydrazinoiminomethyl)hydrazino) acetic acid;    -   (20) PNU 106817 (2-(hydrazinoiminomethyl)hydrazino) acetic acid;    -   (21) NC 2100        (5-((7-(phenylmethoxy)-3-quinolinyl)methyl)-2,4-thiazolidinedione;    -   (22) MXC 3255;    -   (23) MBX 102;    -   (24) ALT 4037;    -   (25) AM 454;    -   (26) JTP 20993        (2-(4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)benzyl)-malonic        acid dimethyl diester);    -   (27) Dexlipotam (5-(R)-(1,2-dithiolan-3-yl)pentanoic acid, also        known as (R)-alpha lipoic acid or (R)-thioctic acid);    -   (28) BM 170744 (2,2-Dichloro-12-(p-chlorophenyl)dodecanoic        acid);    -   (29) BM 152054        (5-(4-(2-(5-methyl-2-(2-thienyl)oxazol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazolidine-2,4-dione);    -   (30) BM 131258        (5-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazolidine-2,4-dione);    -   (31) CRE 16336 (EML 16336);    -   (32) HQL 975        (3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2        (S)-(propylamino)propionic acid);    -   (33) DRF 2189        (5-((4-(2-(1-Indolyl)ethoxy)phenyl)methyl)thiazolidine-2,4-dione);    -   (34) DRF 554158;    -   (35) DRF-NPCC;    -   (36) CLX 0100, CLX 0101, CLX 0900, or CLX 0901;    -   (37) IkappaB Kinase (IKK B) Inhibitors    -   (38) mitogen-activated protein kinase (MAPK) inhibitors p38 MAPK        Stimulators    -   (39) phosphatidyl-inositide triphosphate    -   (40) insulin recycling receptor inhibitors    -   (41) glucose transporter 4 modulators    -   (42) TN F-α antagonists    -   (43) plasma cell differentiation antigen-1 (PC-1) Antagonists    -   (44) adipocyte lipid-binding protein (ALBP/aP2) inhibitors    -   (45) phosphoglycans    -   (46) Galparan;    -   (47) Receptron;    -   (48) islet cell maturation factor;    -   (49) insulin potentiating factor (IPF or insulin potentiating        factor-1);    -   (50) somatomedin C coupled with binding protein (also known as        IGF-BP3, IGF-BP3, SomatoKine);    -   (51) Diab II (known as V-411) or Glucanin, produced by Biotech        Holdings Ltd. or Volque Pharmaceutical;    -   (52) glucose-6 phosphatase inhibitors;    -   (53) fatty acid glucose transport protein;    -   (54) glucocorticoid receptor antagonists; and    -   (55) glutamine:fructose-6-phosphate amidotransferase (GFAT)        modulators.

(C) Biguanides, which decrease liver glucose production and increasesthe uptake of glucose. Examples include metformin such as:

-   -   (1) 1,1-dimethylbiguanide (e.g., Metformin-DepoMed,        Metformin-Biovail Corporation, or METFORMIN GR (metformin        gastric retention polymer)); and    -   (2) metformin hydrochloride (N,N-dimethylimidodicarbonimidic        diamide monohydrochloride, also known as LA 6023, BMS 207150,        GLUCOPHAGE, or GLUCOPHAGE XR.

(D) Alpha-glucosidase inhibitors, which inhibit alpha-glucosidase.Alpha-glucosidase converts fructose to glucose, thereby delaying thedigestion of carbohydrates. The undigested carbohydrates aresubsequently broken down in the gut, reducing the post-prandial glucosepeak. Examples include, but are not limited to:

-   -   (1) acarbose (D-glucose,        0-4,6-dideoxy-4-(((1S-(1alpha,4alpha,5beta,6alpha))-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-,        also known as AG-5421, Bay-g-542, BAY-g-542, GLUCOBAY, PRECOSE,        GLUCOR, PRANDASE, GLUMIDA, or ASCAROSE);    -   (2) Miglitol (3,4,5-piperidinetriol,        1-(2-hydroxyethyl)-2-(hydroxymethyl)-, (2R (2alpha, 3beta,        4alpha, 5beta))-or        (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl-3,4,5-piperidinetriol,        also known as BAY 1099, BAY M 1099, BAY-m-1099, BAYGLITOL,        DIASTABOL, GLYSET, MIGLIBAY, MITOLBAY, PLUMAROL);    -   (3) CKD-711        (0-4-deoxy-4-((2,3-epoxy-3-hydroxymethyl-4,5,6-trihydroxycyclohexane-1-yl)amino)-alpha-b-glucopyranosyl-(1-4)-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose);    -   (4) emiglitate        (4-(2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl)ethoxy)benzoic        acid ethyl ester, also known as BAY o 1248 or MKC 542);    -   (5) MOR 14 (3,4,5-piperidinetriol, 2-(hydroxymethyl)-1-methyl-,        (2R-(2alpha,3beta,4alpha,5beta))-, also known as        N-methyldeoxynojirimycin or N-methylmoranoline); and    -   (6) Voglibose        (3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)-D-epi-inositol        or        D-epi-Inositol,3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)-,        also known as A 71100, AO 128, BASEN, GLUSTAT, VOGLISTAT.

(E) Insulins include regular or short-acting, intermediate-acting, andlong-acting insulins, non-injectable or inhaled insulin, tissueselective insulin, glucophosphokinin (D-chiroinositol), insulinanalogues such as insulin molecules with minor differences in thenatural amino acid sequence and small molecule mimics of insulin(insulin mimetics), and endosome modulators. Examples include, but arenot limited to:

-   -   (1) Biota;    -   (2) LP 100;    -   (3) (SP-5-21)-oxobis (1-pyrrolidinecarbodithioato-S,S′)        vanadium,    -   (4) insulin aspart (human insulin (28B-L-aspartic acid) or        B28-Asp-insulin, also known as insulin X14, INA-X14, NOVORAPID,        NOVOMIX, or NOVOLOG);    -   (5) insulin detemir (Human        29B-(N-6-(1-oxotetradecyl)-L-lysine)-(1A-21A), (1B-29B)-Insulin        or NN 304);    -   (6) insulin lispro (“28B-L-lysine-29B-L-proline human insulin,        or Lys(B28), Pro(B29) human insulin analog, also known as        lys-pro insulin, LY 275585, HUMALOG, HUMALOG MIX 75/25, or        HUMALOG MIX 50/50);    -   (7) insulin glargine (human (A21-glycine, B31-arginine,        B32-arginine) insulin HOE 901, also known as LANTUS, OPTISULIN);    -   (8) Insulin Zinc Suspension, extended (Ultralente), also known        as HUMULIN U or ULTRALENTE;    -   (9) Insulin Zinc suspension (Lente), a 70% crystalline and 30%        amorphous insulin suspension, also known as LENTE ILETIN II,        HUMULIN L, or NOVOLIN L;    -   (10) HUMULIN 50/50 (50% isophane insulin and 50% insulin        injection);    -   (11) HUMULIN 70/30 (70% isophane insulin NPH and 30% insulin        injection), also known as NOVOLIN 70/30, NOVOLIN 70/30 PenFill,        NOVOLIN 70/30 Prefilled;    -   (12) insulin isophane suspension such as NPH ILETIN II, NOVOLIN        N, NOVOLIN N PenFill, NOVOLIN N Prefilled, HUMULIN N;    -   (13) regular insulin injection such as ILETIN II Regular,        NOVOLIN R, VELOSULIN BR, NOVOLIN R PenFill, NOVOLIN R Prefilled,        HUMULIN R, or Regular U-500 (Concentrated);    -   (14) ARIAD;    -   (15) LY 197535;    -   (16) L-783281; and    -   (17) TE-17411.    -   (F) Insulin secretion modulators such as:    -   (1) glucagon-like peptide-1 (GLP-1) and its mimetics;    -   (2) glucose-insulinotropic peptide (GIP) and its mimetics;    -   (3) exendin and its mimetics;    -   (4) dipeptyl protease (DPP or DPPIV) inhibitors such as        -   (4a) DPP-728 or LAF 237            (2-pyrrolidinecarbonitrile,1-(((2-((5-cyano-2-pyridinyl)amino)ethyl)amino)acetyl),            known as NVP-DPP-728, DPP-728A, LAF-237);        -   (4b) P 3298 or P32/98            (di-(3N-((2S,3S)-2-amino-3-methyl-pentanoyl)-1,3-thiazolidine)            fumarate);        -   (4c) TSL 225            (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic            acid);        -   (4d) Valine pyrrolidide (valpyr);        -   (4e) 1-aminoalkylisoquinolinone-4-carboxylates and analogues            thereof;        -   (4f) SDZ 272-070 (1-(L-Valyl)pyrrolidine);        -   (4g) TMC-2A, TMC-2B, or TMC-2C;        -   (4h) Dipeptide nitriles (2-cyanopyrrolodides);        -   (4i) CD26 inhibitors; and        -   (4j) SDZ 274-444;    -   (5) glucagon antagonists such as AY-279955; and    -   (6) amylin agonists which include, but are not limited to,        pramlintide (AC-137, Symlin, tripro-amylin or pramlintide        acetate).

The present compounds may also increase insulin sensitivity with littleor no increase in body weight than that found with the use of existingPPAR gamma agonists. Oral anti-diabetic agents may include insulin,sulfonylureas, biguanides, meglitinides, AGI's, PPAR alpha agonists, andPPAR gamma agonists, and dual PPAR alpha/gamma agonists.

The present compounds also may increase fat and/or lipid metabolism,providing a method for losing weight, losing fat weight, lowering bodymass index, lowering lipids (such as lowering triglycerides), ortreating obesity or the condition of being overweight. Examples of lipidlowering agents include bile acid sequestrants, fibric acid derivatives,nicotinic acid, and HMGCoA reductase inhibitors. Specific examplesinclude statins such as LIPITOR®, ZOCOR®, PRAVACHOL®, LESCOL®, andMEVACOR®, and pitavastatin (nisvastatin) (Nissan, Kowa Kogyo, Sankyo,Novartis) and extended release forms thereof, such as ADX-159 (extendedrelease lovastatin), as well as Colestid, Locholest, Questran, Atromid,Lopid, and Tricor.

Examples of blood pressure lowering agents include anti-hypertensiveagents, such as angiotensin-converting enzyme (ACE) inhibitors(Accupril, Altace, Captopril, Lotensin,Mavik, Monopril, Prinivil,Univasc, Vasotec, and Zestril), adrenergic blockers (such as Cardura,Dibenzyline, Hylorel, Hytrin, Minipress, and Minizide) alpha/betaadrenergic blockers (such as Coreg, Normodyne, and Trandate), calciumchannel blockers (such as Adalat, Calan, Cardene, Cardizem, Covera-HS,Dilacor, DynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia,Procardia XL, Sula, Tiazac, Vascor, and Verelan), diuretics, angiotensinII receptor antagonists (such as Atacand, Avapro, Cozaar, and Diovan),beta adrenergic blockers (such as Betapace, Blocadren, Brevibloc,Cartrol, Inderal, Kerlone, Lavatol, Lopressor, Sectral, Tenormin,Toprol-XL, and Zebeta), vasodilators (such as Deponit, Dilatrate, SR,Imdur, Ismo, Isordil, Isordil Titradose, Monoket, Nitro-Bid, Nitro-Dur,Nitrolingual Spray, Nitrostat, and Sorbitrate), and combinations thereof(such as Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzide,Uniretic, Vaseretic, Zestoretic).

F. Biological Examples

Transfection Assay Method for PPAR Receptors

HEK293 cells were grown in DMEM/F-12 Media supplemented with 10% FBS andglutamine (GIBCOBRL). The cells were co-transfected with DNA forPPAR-Gal4 (PPARα, γ or δ) receptor and Gal4-Luciferase Reporter usingthe DMRIE-C Reagent. On the following day, the medium was replaced with5% Charcoal treated FBS growth medium. After six hours, cells weretrypsinized and seeded at a density of 50,000 cell/well into 96 wellplates and incubated overnight at 37° C. in a 5% CO₂ incubator. Cellswere then treated with test compounds or vehicle and incubated for 24hours at 37° C. in a 5% CO₂ incubator. Luciferase activity was assayedusing the Steady-Glo Luciferase Assay Kit from Promega. DMRIE-C Reagentwas purchased from GIBCO Cat. No. 10459-014. OPTI-MEM I Reduced SerumMedium was purchased from GIBCO Cat. No. 31985. Steady-Glo LuciferaseAssay Kit was purchased from Promega Part# E254B.

A variety of example compounds have been made and tested, with a rangeof in vitro results. Below are representative compounds and data; insome cases, where multiple EC₅₀'s are shown, multiple measurements weretaken. Naturally, different compounds in Formula (I) may have not haveactivities identical to any one compound below.

TABLE 2 In Vitro Data Compound Number EC₅₀ (PPAR delta) nM 1 9.2, 5.6 20.02, 0.33, 0.03, 0.47, 1.5 3 0.08, 0.04 4 29.6 5 0.02, 0.08, 0.04 0.01,0.36, 0.36 6 3.3, 3.7, 3.3 7 211 8 215 9 16.6, 18.5 10 29, 56 11 5.7 1219.9 13 79 14 16.2, 21.5 15 0.76, 0.56, 0.88, 3.4, 5.0, 1.1 16 22.4,27.5 17 4.2, 3.2, 1.5, 4.5, 0.69, 2.7 18 4.3, 4.3 19 7.5, 6.5 20 3.4,14.6, 1.4 21 3.7, 4.2 22 1.3, 2.6, 1.4, 2.1, 4.2, 2.3 23 70 24 6.3, 6.6,5.1, 6.6, 6.4, 3.7 25 25.2, 8.9, 8.8 26 126 27 11.9, 18.5 28 57.3, 67.829 62.1 30 23.9 31 >1000 32 11.2, 11.2 33 4.7, 4.6 34 16.3, 17.7 35 2.3,4.1 36 52.9 37 1.9, 2.9 38 6.9, 7.7, 19.7, 6.5, 4.6 39 12.5, 17.9 4039.3, 43.7 41 144 42 8.0, 7.9 43 43.2 44 24.3 45 618.3

The compounds in Table 3 are also of interest, which have been made andtested likewise:

TABLE 3 Compounds of Interest EC₅₀ (PPAR delta) Structure Physical DatanM

¹H NMR (400 MHz, CD₃OD) δ 7.50-7.58 (m, 8 H), 6.98-7.08 (m, 6 H), 4.74(s, 2 H), 4.73 (s, 2 H), 4.06- 4.22 (m, 4 H), 3.84 (m, 2 H), 3.73 (m, 1H), 3.58 (m, 1 H), 3.46 (m, 1 H), 3.23- 3.36 (m, 3 H), 3.13 (m, 2 H),2.33 (s, 3 H), 2.31 (s, 3H), 1.24 (t, J = 7.0 Hz, 3 H), 1.12 (t, J = 7.0Hz, 3H); MS (ES) m/z: 459 (M − H⁺). >3000

¹H NMR (300 MHz, CDCl₃) δ 7.51 (d, J = 8.7 Hz, 2 H), 7.19 (m, 2 H), 6.91(d, J = 8.5 Hz, 2 H), 6.62 (d, J = 8.4 Hz, 1H), 4.56 (s, 2 H), 4.07 (t,J = 5.3 Hz, 2 H), 3.01 (t, J = 7.0 Hz, 2 H), 2.21 (s, 3 H), 2.06 (m, 2H); MS (ES) m/z: 423 (M + Na⁺). 17.6G. Other Embodiments

The features and principles of the invention are illustrated in thediscussion, examples, and claims herein. Various adaptations andmodifications of the invention will be apparent to a person of ordinaryskill in the art and such other embodiments are also within the scope ofthe invention. Publications cited herein are incorporated in theirentirety by reference.

The invention claimed is:
 1. A method for treating or inhibiting theprogression of a PPAR-delta mediated condition, said method comprisingadministering to a patient in need of treatment a pharmaceuticallyeffective amount of a compound of Formula (II):

wherein X is O; Y is S or O; - - - - - W - - - - - represents a groupselected from —CH═, —CH₂—, —CH₂—CH₂—, —CH₂—CH═, and —CH═CH—; Z isselected from O, CH, and CH₂, provided when Y is O, Z is O; R₁ and R₂are independently selected from H, C₁₋₃ alkyl, C₁₋₃ alkoxy, halo, andNR_(a)R_(b) wherein R_(a) and R_(b) are independently H or C₁₋₃ alkyl;R₃ and R₄ are independently selected from H, halo, cyano, hydroxy,acetyl, C₁₋₅ alkyl, C₁₋₄ alkoxy, and NR_(c)R_(d) wherein R_(c) and R_(d)are independently H or C₁₋₃ alkyl, provided that R₃ and R₄ are not bothH; n is 1 or 2; or a pharmaceutically acceptable salt thereof.
 2. Themethod of claim 1, wherein the PPAR-delta mediated condition is selectedfrom the group consisting of diabetes, cardiovascular diseases,Metabolic X Syndrome, hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity.3. The method of claim 1 wherein Y is O.
 4. The method of claim 1wherein Y is S.
 5. The method of claim 1 wherein Z is O.
 6. The methodof claim 1 wherein Z is CH or CH₂.
 7. The method of claim 1wherein - - - W - - - represents —CH₂— or —CH₂—CH₂—.
 8. The method ofclaim 1 wherein - - - - - W - - - - - represents —CH═, —CH₂—CH═, or—CH═CH—.
 9. The method of claim 1 wherein R₃ and R₄ are independentlyselected from H, halo, cyano, C₁₋₄ alkyl, and C₁₋₃ alkoxy.
 10. Themethod of claim 1 wherein R₁ and R₂ are independently selected from H,C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, and Br.
 11. The method of claim 1wherein R₃ and R₄ are independently selected from H, halo, cyano,hydroxy, C₂₋₄acyl, C₁₋₄ alkyl, and C₁₋₃ alkoxy.
 12. The method of claim1 wherein R₃ is selected from methyl, methoxy, H, Cl, Br, I, OH,—CH(CF₃)₂, CF₃, —OCF₃, —N(CH₃)₂, —O—CH₂COOH, and —COCH₃, and R₄ isselected from H, Cl, and methyl.
 13. The method of claim 1 wherein R₃ isselected from H, F, Cl, methyl, and methoxy, and R₄ is selected from F,Cl, methyl, fluoromethyl, difluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethyl, trifluoromethoxy, and methoxy.
 14. Themethod of claim 1 wherein R₁ is selected from H, CF₃, methyl, Cl, andmethoxy, and R₂ is selected from H, Cl, and methyl.
 15. The method ofclaim 1 wherein Y is O and Z is O.
 16. The method of claim 1 wherein Yis S and Z is O.
 17. The method of claim 1 wherein R₁ is selected fromH, CF₃, methyl, Cl, and methoxy; R₂ is selected from H, Cl, and methyl;R₃ is selected from H, F, Cl, methyl, and methoxy; and R₄ is selectedfrom F, Cl, methyl, trifluoromethyl, trifluoromethoxy, fluoromethyl,fluoromethoxy, difluoromethyl, difluoromethoxy, and methoxy.
 18. Themethod of claim l wherein Y is O; R₃ is selected from H, F, Cl, methyl,and methoxy; and R₄ is selected from F, Cl, methyl, CF₃, OCF₃ andmethoxy.